Publications by authors named "Christiane Wolf"

58 Publications

Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn's disease and active smoking status resulting in ileal stenosis requiring surgery.

PLoS One 2020 27;15(7):e0236421. Epub 2020 Jul 27.

Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.

Background: NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort.

Methods: 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses.

Results: Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery.

Conclusion: Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236421PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384669PMC
September 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Mol Psychiatry 2021 Aug 11;26(8):4179-4190. Epub 2019 Nov 11.

Department of Psychology, Humboldt-University Berlin, Berlin, Germany.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10  × 10). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
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http://dx.doi.org/10.1038/s41380-019-0590-2DOI Listing
August 2021

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Nat Commun 2019 10 8;10(1):4558. Epub 2019 Oct 8.

Durham VA Medical Center, Research, Durham, NC, USA.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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http://dx.doi.org/10.1038/s41467-019-12576-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783435PMC
October 2019

A Candidate Gene Association Study of FKBP5 and CRHR1 Polymorphisms in Relation to War-Related Posttraumatic Stress Disorder.

Psychiatr Danub 2019 Jun;31(2):269-275

Department of Psychiatry, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia,

Background: Posttraumatic stress disorder (PTSD) is a highly frequent and disabling psychiatric condition among war-affected populations. The FK506-binding protein 5 (FKBP5) gene and the corticotropin-releasing hormone receptor 1 (CRHR1) gene have previously been implicated in an elevated risk of peritraumatic dissociation and PTSD development. Our aim was to investigate the association between FKBP5 and CRHR1 genotypes and PTSD diagnosis and severity among individuals who were affected by the Balkan wars during the 1990s.

Subjects And Methods: This study included participants with current PTSD, remitted PTSD and healthy volunteers (N=719, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). FKBP5 rs1360780 and CRHR1 rs17689918 genotypes were determined using a KASP genotyping assay.

Results: Tests for deviation from Hardy Weinberg equilibrium showed no significant results. Logistic and linear regression was used to examine the associations between the FKBP5 SNP rs1360780 and the CRHR1 SNP rs17689918 with PTSD diagnosis and severity, as well as general psychiatric symptom severity, separately for current and remitted PTSD patients. There were nominally significant associations under a dominant model between the rs1360780 C allele and PTSD diagnosis as well as symptom severity, which however, were not significant anymore after Bonferroni adjustment (α=0.002). For CRHR1 rs17689918 no significant associations were detected.

Conclusion: We found nominally, but not Bonferroni corrected significant associations between the FKBP5 polymorphism rs1360780 and PTSD susceptibility among individuals affected by the Balkan wars. For elucidating this gene's real resilience/vulnerability potential, environmental influences should be taken into account.
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http://dx.doi.org/10.24869/psyd.2019.269DOI Listing
June 2019

The Role of TaqI DRD2 (rs1800497) and DRD4 VNTR Polymorphisms in Posttraumatic Stress Disorder (PTSD).

Psychiatr Danub 2019 Jun;31(2):263-268

Department of Psychiatry, University Clinical Centre of Kosovo, Prishtina, Kosovo,

Background: Posttraumatic stress disorder (PTSD) is a complex stress related disorder, that follows a severe traumatic experience, characterized with an intense sense of terror, fear, and helplessness. The aim of this study is to identify associations of genetic variations within candidate genes DRD2 and DRD4 with various PTSD related phenotypes. PTSD lifetime and PTSD current subjects were analyzed separately, each of them were analyzed in a Case/Control design, as well as regarding BSI and CAPS within cases only.

Subjects And Methods: 719 (487 male, 232 female) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Hercegovina, Kosovo and Croatia were included in the study. Sociodemographic questionnaire, Clinician Administered PTSD Scale (CAPS) and the Brief Symptom Inventory (BSI) were used to collect clinical data.

Results: The DRD2 rs1800497 variant and a variable number tandem repeat (VNTR) located in exon three of DRD4 were investigated for association with PTSD. In case control analyses we did not identify any significant associations. Within the PTSD current patients, we identified an association of DRD2 rs1800497 with BSI in the genotypic and the recessive model with the T allele as the risk allele.

Conclusion: Our findings suggest that rs1800497 of DRD2 gene is involved in pathogenesis of PTSD.
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http://dx.doi.org/10.24869/psyd.2019.263DOI Listing
June 2019

Role of the Allelic Variation in the 5-Hydroxytryptamine Receptor 1A (HTR1A) and the Tryptophan Hydroxylase 2 (TPH2) Genes in the Development of PTSD.

Psychiatr Danub 2019 Jun;31(2):256-262

Department of Psychiatry, University Clinical Centre of Kosovo, Str, Hile Mosi, nr 11, 10000 Prishtina, Kosovo,

Background: Post-traumatic stress disorder (PTSD) is a stress related disorder which can occur in an individual after exposure to a traumatic event. It most commonly co-occurs with depression. The two disorders share not only overlapping symptoms, but also genetic diathesis. The aim of this study was to investigate the potential role of single nucleotide polymorphisms (SNPs) of the two serotonergic candidate genes 5-hydroxytryptamine receptor 1A (HTR1A) and tryptophan hydroxylase 2 (TPH2) in the pathogenesis of PTSD and comorbid psychopathology.

Subjects And Methods: 719 (487 males, 232 females) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Herzegovina, Kosovo and Croatia were included in the study. The Sociodemographic questionnaire, Mini International Neuropsychiatric Interview (M.I.N.I.), Clinician Administered PTSD Scale (CAPS) and Brief Symptom Inventory (BSI) were used to collect clinical data. The SNPs rs6295 (HTR1A), rs11178997 and rs1386494 (TPH2) were investigated for their association with PTSD and comorbid psychopathology.

Results: A nominal significant association was found between the BSI total score in Lifetime PTSD with the SNP rs6295 of the HTR1A gene. The best result was seen in the dominant model (P=0.018), with the minor allele (C) being the risk allele. Several BSI subscores were also associated with the minor (C) allele in Lifetime PTSD. No association was found for the TPH2 SNPs rs11178997 and rs1386494 in relation to PTSD or comorbid psychopathology.

Conclusions: Our findings suggest that rs6295 in the HTR1A gene may contribute to the psychopathology of PTSD.
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http://dx.doi.org/10.24869/psyd.2019.256DOI Listing
June 2019

Association of Neuropeptide S Receptor 1 and Glutamate Decarboxylase 1 Gene Polymorphisms with Posttraumatic Stress Disorder.

Psychiatr Danub 2019 Jun;31(2):249-255

Institute of Kosovo Forensic Psychiatry, University Clinical Centre of Kosovo, Prishtina, Kosovo.

Background: Posttraumatic stress disorder (PTSD) is an anxiety disorder caused by highly traumatic experiences. The aim of this study was to investigate the influence of single nucleotide polymorphisms (SNPs) in the neuropeptide S receptor 1 (NPSR1) and the glutamate decarboxylase 1(GAD1) gene on PTSD and its psychopathological aspects among individuals affected by the Balkan wars during the 90s.

Subjects And Methods: This study was conducted as part of the South Eastern Europe (SEE) study on molecular mechanisms of PTSD. It comprised 719 participants (539 males), including those with current PTSD, remitted PTSD and healthy volunteers. Psychometric evaluation was performed using the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) andthe Brief Symptom Inventory (BSI). We examined NPSR1 single nucleotide polymorphism (SNP) rs324981 and GAD1 variant rs3749034 genotypes. Case-control analyses were carried out using logistical regression to determine genotype differences between all patients that had either current or remitted PTSD and control individuals. To analyse the influence of the analysed SNPs on PTSD severity, we performed linear regression analyses with CAPS and BSI within each of the two patient groups separately. All of the calculations were performed for additive allelic, recessive, dominant and genotypic models.

Results: We observed a nominally significant association for the major allele (G) of GAD1 rs3749034 with an increased risk to develop PTSD in a case control analysis in the recessive model (P=0.0315, odds ratio=0.47, SE=0.35). In contrast, a nominally significant association of the minor allele (A) with higher CAPS scores was identified within the patient group with lifetime PTSD in the dominant model (P=0.0372, β=6.29, SE=2.99). None of these results did withstand correction for multiple tests. No nominal significant results of GAD1 rs3749034 were found with regard to the intensity of psychological BSI symptoms. Case-control analyses of NPSR1 rs324981 revealed a nominally significant higher risk for homozygous T allele carriers to develop PTSD (P=0.0452) in the recessive model. On the other hand, the T allele showed a nominally significant association with higher BSI scores in patients suffering from lifetime PTSD in the recessive model (P=0.0434). Again, these results were not significant anymore after correction for multiple tests. No associations of NPSR1 rs324981 and CAPS score was identified.

Conclusion: The findings of this study provide some evidence that the NPSR1 and GAD1 polymorphisms might play a role in the development of war-related PTSD and its related psychological expressions. Further research is needed to elucidate the interactions of specific gene variants and environmental factors in the development of PTSD.
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http://dx.doi.org/10.24869/psyd.2019.249DOI Listing
June 2019

The Association of Catechol-O-Methyl-Transferase and Interleukin 6 Gene Polymorphisms with Posttraumatic Stress Disorder.

Psychiatr Danub 2019 Jun;31(2):241-248

Department of Clinical Biochemistry, University Clinical Centre of Kosovo, Prishtina, Kosovo.

Background: Posttraumatic stress disorder (PTSD) is a disorder that occurs in some people who have experienced a severe traumatic event. Several genetic studies suggest that gene encoding proteins of catechol-O-methyl-transferase (COMT) may be relevant for the pathogenesis of PTSD. Some researchers suggested that the elevation of interleukin-6 (IL6) correlates with major depression and PTSD. The aim of this study was to investigate whether the single nucleotide polymorphisms COMT rs4680 (Val158Met) and IL6 rs1800795 are associated with PTSD and contribute to the severity of PTSD symptoms.

Subjects And Methods: This study comprised 747 participants that experienced war between 1991 and 1999 in the South Eastern Europe conflicts. COMT rs4680 (Val158Met) and IL6 rs1800795 genotypes were determined in 719 participants (369 with and 350 without PTSD). The Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) questionnaire and the Brief Symptom Inventory (BSI) were used for data collection.

Results: Regarding the COMT gene polymorphism, the results of the regression analyses for BSI total score were significant in the lifetime PTSD group in the dominant (P=0.031) and the additive allelic model (P=0.047). Regarding the IL6 gene, a significant difference was found for the recessive model predicting CAPS total score in the lifetime PTSD group (P=0.048), and indicated an association between the C allele and higher CAPS scores. n the allelic, genotypic and rezessive model, the results for BSI total score were significant in the lifetime PTSD group (P=0.033, P=0.028 and P=0.009), suggesting a correlation of the C allele with higher BSI scores.

Conclusion: Although our nominally significant results did not withstand correction for multiple tests they may support a relevance of the COMT (Val158Met) and IL6 rs1800795 polymorphism for aspects of PTSD in war traumatized individuals.
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http://dx.doi.org/10.24869/psyd.2019.241DOI Listing
June 2019

Associations between Polymorphisms in the Solute Carrier Family 6 Member 3 and the Myelin Basic Protein Gene and Posttraumatic Stress Disorder.

Psychiatr Danub 2019 Jun;31(2):235-240

Community Health Center Zivinice, Alije Izetbegovica 17, 75270 Zivinice, Bosnia & Herzegovina,

Background: Previous research showed inconsistent results concerning a possible association between solute carrier family 6 member 3 (SLC6A3) gene polymorphisms and dopamine symptoms of posttraumatic stress disorder (PTSD). Several studies also indicate that the myelin basic protein (MBP) gene is of importance in the etiology of several psychiatric disorders. The aim of this study was to investigate the relation of distinct SLC6A3 and MBP gene polymorphisms with PTSD and whether SLC6A3 and MBP genotypes contribute to PTSD symptom severity.

Subjects And Methods: The study included 719 individuals who had experienced war trauma in the South Eastern Europe (SEE). Genotypes of variable number tandem repeat (VNTR) polymorphism within the SLC6A3 gene were assessed in 696 participants, and the single nucleotide polymorphism (SNP) rs12458282 located within the MBP gene region was genotyped in a total of 703 subjects. The Mini International Neuropsychiatric Interview, the Clinical Administrated PTSD Scale (CAPS) and Brief Symptom Inventory (BSI), were used for data collection.

Results: No significant differences concerning the investigated SLC6A3 and MBP polymorphisms was identifiable between PTSD and non PTSD participants. Also we could not detect significant influence of these distinct SLC6A3 and MBP alleles on the severity of PTSD symptoms (CAPS) or BSI scores. However, the results of MBP rs12458282 within the patients with lifetime PTSD may point to a possible correlation of the major allele (T) with elevated CAPS scores.

Conclusions: Our results do not support an association of the analysed SLC6A3 and MBP gene polymorphisms with PTSD in war traumatized individuals. We found that there is a possibility for a correlation of the T allele rs12458282 within the MBP gene with higher CAPS scores in lifetime PTSD patients which would need to be tested in a sample providing more statistical power.
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http://dx.doi.org/10.24869/psyd.2019.235DOI Listing
June 2019

Associations of Gene Variations in Neuropeptide Y and Brain Derived Neurotrophic Factor Genes with Posttraumatic Stress Disorder.

Psychiatr Danub 2019 Jun;31(2):227-234

International Burch University, Department of Genetics and Bioengineering, Francuske revolucije bb, 71000 Sarajevo, Bosnia and Herzegovina,

Background: Individuals who are exposed to traumatic events are at an increased risk of developing posttraumatic stress disorder (PTSD), a condition during which an individual's ability to function is impaired by emotional responses to memories of those events. The gene coding for neuropeptide Y (NPY) and the gene coding for brain-derived neurotrophic factor (BDNF) are among the number of candidate gene variants that have been identified as potential contributors to PTSD. The aim of this study was to investigate the association between NPY and BDNF and PTSD in individuals who experienced war-related trauma in the South Eastern Europe (SEE) conflicts (1991-1999).

Subjects And Methods: This study included participants with current and remitted PTSD and healthy volunteers (N=719, 232 females, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administered PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). DNA was isolated from whole blood and genotyped for NPY rs5574 via PCR - RFLP and NPY rs16147 and BDNF rs6265 using the KASP assay.

Results: Tests for deviation from Hardy-Weinberg equilibrium showed no significant results. Analyses at the categorical level yielded no associations between the affected individuals and all three SNPs when compared to controls. Within lifetime PTSD patients, the major alleles of both NPY variants showed a nominally significant association with higher CAPS scores (p=0.007 and p=0.02, respectively). Also, the major allele of rs5574C>T was associated with higher BSI scores with a nominal significance among current PTSD patients (p=0.047). The results did not withstand a Bonferroni adjustment (α=0.002).

Conclusion: Nominally significant associations between NPY polymorphisms and PTSD susceptibility were found that did not withstand Bonferroni correction.
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http://dx.doi.org/10.24869/psyd.2019.227DOI Listing
June 2019

Genetic Susceptibility to Posttraumatic Stress Disorder: Analyses of the Oxytocin Receptor, Retinoic Acid Receptor-Related Orphan Receptor A and Cannabinoid Receptor 1 Genes.

Psychiatr Danub 2019 Jun;31(2):219-226

Department of Psychiatry, Clinical Center University Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina,

Background: Exposure to life-threatening events is common and everyone will most likely experience this type of trauma during their lifetime. Reactions to these events are highly heterogeneous and seems to be influenced by genes as well. Some individuals will develop posttraumatic stress disorder (PTSD), while others will not. In this study, our aim was to analyze the correlation between single nucleotide polymorphisms (SNPs) within the oxytocin receptor (OXTR) gene (rs53576 and rs2254298), the RAR-related orphan receptor A (RORA) gene (rs8042149) and the cannabinoid receptor 1 (CNR1) gene (rs1049353) and PTSD. All candidate genes have been previously associated with stress related disorders and the reaction to traumatic events.

Subjects And Methods: Participants (N=719) have been exposed to war-related trauma during the war in South-Eastern Europe (Bosnia and Herzegovina, Croatia and Kosovo). We correlated the presence and absence of current and lifetime PTSD as well as PTSD severity (Clinician Administered PTSD scale (CAPS)) and current psychopathology (Brief Symptom Inventory (BSI) score) with the mentioned SNPs. DNA was isolated from whole blood and genotyped for OXTR rs2254298 and rs53576 following previously published protocols, for RORA rs8042149 via PCR-RFLP and CNR1 rs1049353 via KASP.

Results: Nominally significant results were found for OXTR rs53576 in connection with the CAPS and BSI scores within lifetime PTSD patients. The additive allelic model indicated that G allele carriers achieved lower CAPS (p=0.0090) and BSI (p=0.0408) scores than participants carrying one or two copies of the A allele. These results did not withstand correction for multiple tests. No significant results were observed for OXTR rs2254298, RORA rs8042149 and CNR1 rs1049353 although the results for RORA showed a slight tendency that rs8042149 may influence the level of BSI scores in current PTSD patients.

Conclusions: This study points to a role of the OXTR gene in PTSD and the related psychopathology following war related trauma.
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http://dx.doi.org/10.24869/psyd.2019.219DOI Listing
June 2019

Association Analysis of Maoa and Slc6a4 Gene Variation in South East European War Related Posttraumatic Stress Disorder.

Psychiatr Danub 2019 Jun;31(2):211-218

Department of Psychiatry, University Clinical Centre Tuzla, Rate Dugonjića bb, 75000 Tuzla, Bosnia and Herzegovina,

Background: The aim of this study is to investigate the association of gene variations of the monoamine oxidase A (MAOA) and the serotonin transporter solute carrier family 6 member 4 (SLC6A4) gene with posttraumatic stress disorder (PTSD) severity and coping strategies in patients with war related PTSD.

Subjects And Methods: The study included 747 individuals who had experienced war trauma in the South Eastern Europe conflicts between 1991 and 1999. Genotyping of the MAOA VNTR and SLC6A4 tandem repeat polymorphism in combination with rs25531 was done in 719 participants: 232 females and 487 males. Among them, 369 have had current or lifetime PTSD and 350 have had no PTSD symptoms. For psychometric approach we used the Clinician Administrated PTSD Scale (CAPS), the Brief Symptom Inventory (BSI), the adapted Hoffman-Lazarus Coping scale and a basic socio-demographic data questionnaire.

Results: There were no significant intergroup (PTSD versus non PTSD) differences in the genotype distribution of MAOA and SLC6A4 gene polymorphisms. The primary finding of our study was that the MAOA short allele (MAOA-S) was nominally significantly associated with the severity of PTSD symptoms in the total subgroup of participants with lifetime PTSD; males for symptoms of hyperarrousal and females with symptoms of re-experience and hyperarousal. In our research the male subsample with current PTSD and MAOA-S genotype had nominally significantly higher scores for some positive coping strategies compared to those carrying the long allele genotype (MAOA-L). There was no significant association between the severity of PTSD symptoms, BSI phenotype, coping scores and the SLC6A4 genotype.

Conclusion: The present results support the notion that MAOA VNTR gene variation modulates development and recovery of posttraumatic stress disorder in a war traumatised population, but did not support a connection between SLC6A4 gene variations and war related PTSD.
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http://dx.doi.org/10.24869/psyd.2019.211DOI Listing
June 2019

A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders.

Transl Psychiatry 2019 05 23;9(1):150. Epub 2019 May 23.

Neurogenetics Unit, Center for Molecular Medicine, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
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http://dx.doi.org/10.1038/s41398-019-0481-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533285PMC
May 2019

Monoamine Oxidase A Gene Methylation and Its Role in Posttraumatic Stress Disorder: First Evidence from the South Eastern Europe (SEE)-PTSD Study.

Int J Neuropsychopharmacol 2018 05;21(5):423-432

Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.

Background: Posttraumatic stress disorder is characterized by an overactive noradrenergic system conferring core posttraumatic stress disorder symptoms such as hyperarousal and reexperiencing. Monoamine oxidase A is one of the key enzymes mediating the turnover of noradrenaline. Here, DNA methylation of the monoamine oxidase A gene exonI/intronI region was investigated for the first time regarding its role in posttraumatic stress disorder risk and severity.

Methods: Monoamine oxidase A methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells in a total sample of N=652 (441 male) patients with current posttraumatic stress disorder, patients with remitted posttraumatic stress disorder, and healthy probands (comparison group) recruited at 5 centers in Bosnia-Herzegovina, Croatia, and the Republic of Kosovo. Posttraumatic stress disorder severity was measured by means of the Clinician-Administered Posttraumatic Stress Disorder Scale and its respective subscores representing distinct symptom clusters.

Results: In the male, but not the female sample, patients with current posttraumatic stress disorder displayed hypermethylation of 3 CpGs (CpG3=43656362; CpG12=43656514; CpG13=43656553, GRCh38.p2 Assembly) as compared with remitted Posttraumatic Stress Disorder patients and healthy probands. Symptom severity (Clinician-Administered Posttraumatic Stress Disorder Scale scores) in male patients with current posttraumatic stress disorder significantly correlated with monoamine oxidase A methylation. This applied particularly to symptom clusters related to reexperiencing of trauma (cluster B) and hyperarousal (cluster D).

Conclusions: The present findings suggest monoamine oxidase A gene hypermethylation, potentially resulting in enhanced noradrenergic signalling, as a disease status and severity marker of current posttraumatic stress disorder in males. If replicated, monoamine oxidase A hypermethylation might serve as a surrogate marker of a hyperadrenergic subtype of posttraumatic stress disorder guiding personalized treatment decisions on the use of antiadrenergic agents.
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http://dx.doi.org/10.1093/ijnp/pyx111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932467PMC
May 2018

Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus.

Nat Commun 2017 11 15;8(1):1511. Epub 2017 Nov 15.

Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, 53127, Bonn, Germany.

Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3'-mRNA transcripts of 288 genes. Hippocampal cis-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.
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http://dx.doi.org/10.1038/s41467-017-01818-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688097PMC
November 2017

Interaction between the gene, body mass index and depression: meta-analysis of 13701 individuals.

Br J Psychiatry 2017 08 22;211(2):70-76. Epub 2017 Jun 22.

Margarita Rivera, PhD, Department of Biochemistry and Molecular Biology II and Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain, and MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, Kinǵs College London, UK; Adam E. Locke, PhD, Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA; Tanguy Corre, PhD, Department of Medical Genetics, University of Lausanne, Lausanne, and Swiss Institute of Bioinformatics, Lausanne, Switzerland; Darina Czamara, PhD, Christiane Wolf, PhD, Max Planck Institute of Psychiatry, Munich, Germany; Ana Ching-Lopez, Department of Psychiatry, School of Medicine, University of Granada, and Institute of Neurosciences Federico Olóriz, Centra de Investigación Biomédica, University of Granada, Spain; Yuri Milaneschi, PhD, Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center/GGZ in Geest, Amsterdam, The Netherlands; Stefan Kloiber, MD, Max Planck Institute of Psychiatry, Munich, Germany; Sara Cohen-Woods, PhD, School of Psychology, Flinders University, Adelaide, South Australia, Australia; James Rucker, MD, PhD, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; Katherine J. Aitchison, MD, PhD, Department of Psychiatry, University of Alberta, Alberta, Canada; Sven Bergmann, PhD, Department of Medical Genetics, University of Lausanne, Lausanne, and Swiss Institute of Bioinformatics, Lausanne, Switzerland; Dorret I. Boomsma, PhD, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands; Nick Craddock, MB, PhD, FMedSci, Department of Psychological Medicine and Neurology, Cardiff University School of Medicine, Henry Wellcome Building, Cardiff, UK; Michael Gill, MD, Department of Psychiatry, Trinity Centre for Health Sciences, Dublin 8, Ireland; Florian Holsboer, MD, PhD, Max Planck Institute of Psychiatry, Munich, Germany; Jouke-Jan Hottenga, PhD, Department of Psychiatry, University of Alberta, Alberta, Canada; Ania Korszun, PhD, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Zoltan Kutalik, PhD, Department of Medical Genetics, University of Lausanne, Lausanne, and Swiss Institute of Bioinformatics, Lausanne, Switzerland; Susanne Lucae, MD, PhD, Max Planck Institute of Psychiatry, Munich, Germany; Wolfgang Maier, MD, Department of Psychiatry, University of Bonn, Bonn, Germany; Ole Mors, MD, PhD, Research Department P, Aarhus University Hospital, Risskov, Denmark; Bertram Müller-Myhsok MD, Max Planck Institute of Psychiatry, Munich, Germany; Michael J. Owen, MB, PhD, FMedSci, MRC Centre for Neuropsychiatry Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK; Brenda W. J. H. Penninx, PhD, Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center/GGZ in Geest, Amsterdam, The Netherlands; Martin Preisig, MD, Department of Psychiatry, Lausanne University Hospital, 1008 Prilly-Lausanne, Switzerland; John Rice, PhD, Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA; Marcella Rietschel, MD, Central Institute of Mental Health, Mannheim, Germany; Federica Tozzi, MD, Genetics Division, Drug Discovery, GlaxoSmithKline Research and Development, Verona, Italy; Rudolf Uher, MD, PhD, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK, and Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada; Peter Vollenweider, MD, PhD, Gerard Waeber, MD, PhD, Division of Internal Medicine, CHUV, Lausanne, Switzerland; Gonneke Willemsen, PhD, Department of Psychiatry, University of Alberta, Alberta, Canada; Ian W. Craig, PhD, Anne E. Farmer, MD, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; Cathryn M. Lewis, PhD, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, and Department of Medical and Molecular Genetics, School of Medicine, King's College London, UK; Gerome Breen, PhD, Peter McGuffin, MB, PhD, FMedSci, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the gene, suggesting its implication in the association between depression and obesity.To confirm these findings by investigating the polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.In the replication cohorts, we observed a significant interaction between , BMI and depression with fixed effects meta-analysis (β = 0.12, = 2.7 × 10) and with the Han/Eskin random effects method ( = 1.4 × 10) but not with traditional random effects (β = 0.1, = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, = 0.027) being highly significant based on the Han/Eskin model ( = 6.9 × 10). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of This meta-analysis provides additional support for a significant interaction between , depression and BMI, indicating that depression increases the effect of on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
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http://dx.doi.org/10.1192/bjp.bp.116.183475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537566PMC
August 2017

Novel genetic loci associated with hippocampal volume.

Nat Commun 2017 01 18;8:13624. Epub 2017 Jan 18.

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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http://dx.doi.org/10.1038/ncomms13624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253632PMC
January 2017

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Nat Neurosci 2016 12 3;19(12):1569-1582. Epub 2016 Oct 3.

Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht, the Netherlands.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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http://dx.doi.org/10.1038/nn.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227112PMC
December 2016

Molecular Mechanisms of Posttraumatic Stress Disorder (PTSD) as a Basis for Individualized and Personalized Therapy: Rationale, Design and Methods of the South Eastern Europe (SEE)-PTSD study.

Psychiatr Danub 2016 Jun;28(2):154-63

Department of Psychiatry, University Clinical Center Sarajevo, Bolnicka 25, 71000 Sarajevo, Bosnia and Herzegovina,

Posttraumatic Stress Disorder (PTSD) is a major health problem in South Eastern Europe (SEE). Available treatment options are not efficient enough and the course is often chronic. Little is known about molecular mediators and moderators of pathogenesis and therapy. Genetic and epigenetic variation may be one central molecular mechanism. We therefore established a consortium combining clinical expertise on PTSD from SEE countries Bosnia-Herzegovina (Sarajevo, Tuzla and Mostar), Kosovo (Prishtina) and Croatia (Zagreb) with genetic and epigenetic competence from Germany (Würzburg) in 2011 within the framework of the DAAD (Deutscher Akademischer Austauschdienst)-funded Stability Pact for South Eastern Europe. After obtaining ethical votes and performing rater trainings as well as training in DNA extraction from EDTA blood between 2011 and 2013, we recruited 747 individuals who had experienced war-related trauma in the SEE conflicts between 1991 and 1999. 236 participants had current PTSD, 161 lifetime PTSD and 350 did not have and never had PTSD. Demographic and clinical data are currently merged together with genetic and epigenetic data in a single database to allow for a comprehensive analysis of the role of genetic and epigenetic variation in the pathogenesis and therapy of PTSD. Analyses will be done to a great degree by PhD students from participating SEE centers who in addition to participation in the project had an opportunity to take part in spring and summer schools of the DFG (Deutsche Forschungsgemeinschaft) funded Research Training Group (RTG) 1253 and thus meet PhD students from Germany and other countries We are confident that our project will not only contribute to a better understanding of genetic and epigenetic mechanisms of PTSD as a basis for future individualized and personalized therapies, but also to the academic development of South Eastern Europe.
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June 2016

White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.

Stroke 2015 Nov 8;46(11):3048-57. Epub 2015 Oct 8.

From the Department of Neurology (E.H., M.C., H.S., R.S.) and Institute for Medical Informatics, Statistics and Documentation (E.H.), Medical University of Graz, Graz, Austria; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.), Radiology (D.K.S.), and Neurology and Epidemiology (W.T.L.), University of Washington, Seattle; Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento (C.D.C., O.M.); Brown Foundation Institute of Molecular Medicine (M.F.) and Human Genetics Center (M.F.), University of Texas Health Science Center, Houston; Icelandic Heart Association, Kopavogur, Iceland (S.S., V.G., A.S.); Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia (V.S., M.C., C.M., T.P., R.B.); Departments of Cardiology (S.T., J.W.J.), Gerontology and Geriatrics (S.T., A.J.M.C., R.G.J.W.), Molecular Epidemiology (P.E.S.), and Radiology (M.B.), Leiden University Medical Center, Leiden, The Netherlands; Departments of Epidemiology (B.F.J.V., H.H.H.A., C.M.D., A.H., M.W.V., M.A.I.), Radiology (B.F.J.V., H.H.H.A., M.W.V., M.A.I.), and Medical Informatics (W.J.N.), Erasmus Medical Center, Rotterdam, The Netherlands; INSERM U897 (C.W., G.C., C.D., S.S., S.D.), CNRS-CEA UMR5296 (B.M.), and INSERM U708 (C.T.), Université Bordeaux Segalen, Bordeaux, France; Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany (C.W.); Department of Biostatistics, Boston University School of Public Health, MA (Q.Y., A.B., J.W.); INSERM U744, Pasteur Institute, Lille, France (P.A.); Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland (B.M.B.); INSERM U1161 and Lariboisière Hospital, Paris 7 University, Paris, France (G.C., S.S., S.D.); Centre for Medical Systems Biology, Leiden, The Netherlands (C.M.D.); Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom (I.F

Background And Purpose: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Methods: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

Results: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

Conclusions: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
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http://dx.doi.org/10.1161/STROKEAHA.115.009252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749149PMC
November 2015

Solid Organ Transplantation in Patients with Inflammatory Bowel Diseases (IBD): Analysis of Transplantation Outcome and IBD Activity in a Large Single Center Cohort.

PLoS One 2015 19;10(8):e0135807. Epub 2015 Aug 19.

Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.

Background: Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.

Methods: Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.

Results: 4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10(-6), UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).

Conclusions: SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135807PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545391PMC
May 2016

The NOD2 Single Nucleotide Polymorphism rs72796353 (IVS4+10 A>C) Is a Predictor for Perianal Fistulas in Patients with Crohn's Disease in the Absence of Other NOD2 Mutations.

PLoS One 2015 6;10(7):e0116044. Epub 2015 Jul 6.

Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.

Background: A previous study suggested an association of the single nucleotide polymorphism (SNP) rs72796353 (IVS4+10 A>C) in the NOD2 gene with susceptibility to Crohn's disease (CD). However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD) susceptibility and the IBD phenotype.

Methodology: Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC), and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted.

Results: In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10(-3)), rs2066845 (p=1.54 x 10(-2)), and rs2066847 (p=1.61 x 10(-20)) with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10(-7), OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers).

Conclusion/significance: Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116044PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493062PMC
March 2016

Analyzing pathways from childhood maltreatment to internalizing symptoms and disorders in children and adolescents (AMIS): a study protocol.

BMC Psychiatry 2015 Jun 10;15:126. Epub 2015 Jun 10.

Department of Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, University of Leipzig, Leipzig, Germany.

Background: Effective interventions for maltreated children are impeded by gaps in our knowledge of the etiopathogenic mechanisms leading from maltreatment to mental disorders. Although some studies have already identified individual risk factors, there is a lack of large-scale multilevel research on how psychosocial, neurobiological, and genetic factors act in concert to modulate risk of internalizing psychopathology in childhood following maltreatment. To help close this gap, we aim to delineate gender-specific pathways from maltreatment to psychological disorder/resilience. To this end, we examine the interplay of specific maltreatment characteristics and psychological, endocrine, metabolomic, and (epi-)genomic stress response patterns as well as cognitive-emotional/social processes as determinants of developmental outcome. Specifically, we will explore endocrine, metabolomic, and epigenetic mechanisms leading from maltreatment to a higher risk of depression and anxiety disorders.

Methods/design: Four large samples amounting to a total of N = 920 children aged 4-16 years will be assessed: Two cohorts with prior internalizing psychopathology and controls will be checked for maltreatment and two cohorts with substantiated maltreatment will be checked for internalizing (and externalizing) psychopathology. We will apply a multi-source (interview, questionnaires, official records), multi-informant strategy (parents, children, teachers) to assess maltreatment characteristics (e.g., subtypes, developmental timing, chronicity) and psychopathological symptoms, supplemented with multiple measurements of risk and protective factors and cutting-edge laboratory analyses of endocrine, steroid metabolomic and epigenetic factors. As previous assessments in the two largest samples are already available, longitudinal data will be generated within the three year study period.

Discussion: Our results will lay the empirical foundation for (a) detection of early biopsychosocial markers, (b) development of screening measures, and
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http://dx.doi.org/10.1186/s12888-015-0512-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460761PMC
June 2015

A genetic risk score combining 32 SNPs is associated with body mass index and improves obesity prediction in people with major depressive disorder.

BMC Med 2015 Apr 17;13:86. Epub 2015 Apr 17.

MRC SGDP Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Box PO82, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.

Background: Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD.

Methods: Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case-control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity.

Results: In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P < 0.001) but explained only a modest amount of variance. Adding 'traditional' risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62-0.68; χ(2) = 27.68; P < 0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC = 0.71; 95% CI, 0.68-0.73; χ(2) = 28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results.

Conclusions: A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity.
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http://dx.doi.org/10.1186/s12916-015-0334-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407390PMC
April 2015

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

Circ Cardiovasc Genet 2015 Apr 7;8(2):398-409. Epub 2015 Feb 7.

Background: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

Methods And Results: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

Conclusions: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427240PMC
April 2015

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

Biol Psychiatry 2015 Apr 25;77(8):749-63. Epub 2014 Nov 25.

Max Planck Institute for Intelligent Systems, Tübingen, Germany; Max Planck Institute for Developmental Biology, Tübingen, Germany.

Background: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

Methods: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

Results: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

Conclusions: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
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http://dx.doi.org/10.1016/j.biopsych.2014.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513651PMC
April 2015

Common genetic variants influence human subcortical brain structures.

Nature 2015 Apr 21;520(7546):224-9. Epub 2015 Jan 21.

1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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http://dx.doi.org/10.1038/nature14101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393366PMC
April 2015

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

Nat Genet 2015 Jan 24;47(1):78-83. Epub 2014 Nov 24.

1] Institute of Cardiovascular Research Royal Holloway University of London (ICR2UL), London, UK. [2] Ashford and St Peter's Hospitals, London, UK.

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
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http://dx.doi.org/10.1038/ng.3154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824623PMC
January 2015
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