Publications by authors named "Hans J Grabe"

166 Publications

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

JAMA Intern Med 2021 Sep 7. Epub 2021 Sep 7.

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.

Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.

Design, Setting, And Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.

Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.

Main Outcomes And Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.

Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.

Conclusions And Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
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http://dx.doi.org/10.1001/jamainternmed.2021.5078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424529PMC
September 2021

Cardiac Hypertrophy Is Associated With Advanced Brain Aging in the General Population.

J Am Heart Assoc 2021 Sep 1;10(17):e020994. Epub 2021 Sep 1.

German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald Greifswald Germany.

Background Hypertrophy of the left ventricle (LV) has recently been associated with adverse changes of brain structure in older adults, notably increased burden of white matter hyperintensities (WMHs). Whether greater LV size or mass is also related to WMH burden in middle-aged adults is currently unclear. In addition, its relation with alterations in cortical thickness (CT) has not been studied to date. Methods and Results Data from 1602 participants of the population-based SHIP (Study of Health in Pomerania) with LV ejection fraction >40% and no history of myocardial infarction were included (aged 21-82 years; median age, 49 years; 53% women). Participants underwent both echocardiography and magnetic resonance imaging of the head. Imaging markers of brain aging (ie, CT and WMH volume) were determined from magnetic resonance imaging scans. LV mass and diameter were associated with lower global CT and greater WMH volume, while adjusting for age, sex, body height, fat-free body mass, and intracranial volume. Moreover, thicknesses of the interventricular septum and posterior wall were also associated with lower global CT. These associations could not be explained by cardiovascular risk factors (including hypertension), inflammatory markers, or sociodemographic factors. Regional analyses showed distinct spatial patterns of lower CT in association with LV diameter and posterior wall thickness. Conclusions LV diameter and mass are associated with lower global and regional CT as well as greater WMH burden in the general population. These findings highlight the brain structural underpinnings of the associations of LV hypertrophy with cognitive decline and dementia.
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http://dx.doi.org/10.1161/JAHA.121.020994DOI Listing
September 2021

The relation between childhood adversity and adult obesity in a population-based study in women and men.

Sci Rep 2021 Jul 7;11(1):14068. Epub 2021 Jul 7.

Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Semmelweisstrasse 10, 04103, Leipzig, Germany.

Childhood maltreatment has been shown to relate to adult obesity. In this epidemiological study, we investigate the association between childhood maltreatment and waist-to-height-ratio (WHtR) in a sample of the German adult population, comprising of N = 2936 participants. WHtR, an indicator for risk of obesity, was the primary outcome. Childhood maltreatment was assessed by the Childhood Trauma Screener (CTS), which assesses emotional and physical neglect, abuse as well as sexual abuse. Cohort-data were harmonized and analyzed within DataSHIELD. We used multivariable regression models to estimate the association of childhood maltreatment and WHtR at different levels of adjustments for potential confounders. Overall childhood maltreatment was associated with a higher WHtR in both sexes (women: p = 0.004, men: p < 0.001); associations were no longer significant in women after adding socioeconomic variables, but remained significant in men (p = 0.013). Additionally, we were able to identify sex specific patterns for childhood maltreatment predicting the WHtR. Emotional neglect and abuse had stronger impacts on the WHtR in women than in men, whereas physical neglect and abuse had stronger impacts in men. To our knowledge, this is the first comprehensive population-based study testing various types of childhood maltreatment with WHtR in sex-, region- and weight-stratified analyses. Future studies in clinical populations are warranted to examine U-shaped correlations between increased WHtR and childhood maltreatment.
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http://dx.doi.org/10.1038/s41598-021-93242-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263764PMC
July 2021

Telemedical care and quality of life in patients with schizophrenia and bipolar disorder: results of a randomized controlled trial.

BMC Psychiatry 2021 06 29;21(1):318. Epub 2021 Jun 29.

University Hospital Greifswald, Clinic and Polyclinic for Psychiatry and Psychotherapy, Greifswald, Germany.

Background: Schizophrenia and bipolar disorder are serious psychiatric disorders with a high disease burden, a high number of years of life lived with disability and a high risk for relapses and re-hospitalizations. Besides, both diseases are often accompanied with a reduced quality of life (QoL). A low level of quality of life is one predictor for relapses. This study examines whether a telemedical care program can improve QoL.

Methods: Post stationary telemedical care of patients with severe psychiatric disorders" (Tecla) is a prospective controlled randomized intervention trial to implement and evaluate a telemedical care concept for patients with schizophrenia and bipolar disorder. Participants were randomized to an intervention or a control group. The intervention group received telemedical care including regular, individualized telephone calls and SMS-messages. QoL was measured with the German version of the WHOQOL-BREF. Effects of telemedicine on QoL after 6 months and treatment*time interactions were calculated using linear regressions (GLM and linear mixed models).

Results: One hundred eighteen participants were recruited, thereof 57.6% men (n = 68). Participants were on average 43 years old (SD 13). The treatment*time interaction was not significant. Hence, treatment had no significant effect either. Instead, gender is an influencing factor. Further analysis showed that social support, the GAF-level and QoL-values at baselines were significant determinants for the improvement of QoL.

Conclusion: The telemedicine care concept Tecla was not significant for QoL in patients with severe psychiatric disorders. More important for the QoL is the general social support and the level of global functioning of the patients.

Trial Registration: German Clinical Trials Register, DRKS00008548, registered 21 May 2015 - retrospectively registered, https://www.drks.de/drks_web/setLocale_EN.do.
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http://dx.doi.org/10.1186/s12888-021-03318-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243575PMC
June 2021

Alexithymic But Not Autistic Traits Impair Prosocial Behavior.

J Autism Dev Disord 2021 06 28. Epub 2021 Jun 28.

Department of Sport Science, University of Rostock, Ulmenstr. 69, 18057, Rostock, Germany.

Social impairments are a core feature of autism-spectrum disorders. However, there is a considerable variability in these impairments. Most autistic individuals show large impairments in social functioning but some autistic individuals show small impairments in social functioning. The variability of these impairments has been attributed to the presence or absence of alexithymia. To address this issue, we capitalized on the fact that alexithymic and autistic traits are broadly distributed in the population. This allowed us to investigate how alexithymic and autistic traits affect social functioning in healthy individuals. Healthy individuals showed impairments on a resource-allocation task that were due to alexithymic but not autistic traits. These findings suggest that alexithymic rather than autistic traits impair prosocial behavior across the autism-spectrum.
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http://dx.doi.org/10.1007/s10803-021-05154-xDOI Listing
June 2021

Alexithymic But Not Autistic Traits Impair Prosocial Behavior.

J Autism Dev Disord 2021 06 28. Epub 2021 Jun 28.

Department of Sport Science, University of Rostock, Ulmenstr. 69, 18057, Rostock, Germany.

Social impairments are a core feature of autism-spectrum disorders. However, there is a considerable variability in these impairments. Most autistic individuals show large impairments in social functioning but some autistic individuals show small impairments in social functioning. The variability of these impairments has been attributed to the presence or absence of alexithymia. To address this issue, we capitalized on the fact that alexithymic and autistic traits are broadly distributed in the population. This allowed us to investigate how alexithymic and autistic traits affect social functioning in healthy individuals. Healthy individuals showed impairments on a resource-allocation task that were due to alexithymic but not autistic traits. These findings suggest that alexithymic rather than autistic traits impair prosocial behavior across the autism-spectrum.
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http://dx.doi.org/10.1007/s10803-021-05154-xDOI Listing
June 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

A metabolome-wide association study in the general population reveals decreased levels of serum laurylcarnitine in people with depression.

Mol Psychiatry 2021 Jun 4. Epub 2021 Jun 4.

Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a metabolome-wide association analysis to investigate the link between the serum metabolome and depressed mood (DM) in 1411 participants of the KORA (Cooperative Health Research in the Augsburg Region) F4 study (discovery cohort). Serum metabolomics data comprised 353 unique metabolites measured by Metabolon. We identified 72 (5.1%) KORA participants with DM. Linear regression tests were conducted modeling each metabolite value by DM status, adjusted for age, sex, body-mass index, antihypertensive, cardiovascular, antidiabetic, and thyroid gland hormone drugs, corticoids and antidepressants. Sensitivity analyses were performed in subcohorts stratified for sex, suicidal ideation, and use of antidepressants. We replicated our results in an independent sample of 968 participants of the SHIP-Trend (Study of Health in Pomerania) study including 52 (5.4%) individuals with DM (replication cohort). We found significantly lower laurylcarnitine levels in KORA F4 participants with DM after multiple testing correction according to Benjamini/Hochberg. This finding was replicated in the independent SHIP-Trend study. Laurylcarnitine remained significantly associated (p value < 0.05) with depression in samples stratified for sex, suicidal ideation, and antidepressant medication. Decreased blood laurylcarnitine levels in depressed individuals may point to impaired fatty acid oxidation and/or mitochondrial function in depressive disorders, possibly representing a novel therapeutic target.
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http://dx.doi.org/10.1038/s41380-021-01176-0DOI Listing
June 2021

Alexithymia is associated with reduced vitamin D levels, but not polymorphisms of the vitamin D binding-protein gene.

Psychiatr Genet 2021 Aug;31(4):126-134

Department of Psychiatry and Psychotherapy, HELIOS Hanseklinikum Stralsund, Rostocker Chaussee, Stralsund.

Objective: Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions, which is associated with various psychiatric disorders, including depression and posttraumatic stress disorder (PTSD). Its pathogenesis is incompletely understood but previous studies suggested that genetic as well as metabolic factors, are involved. However, no results on the role of vitamin D and the polymorphisms rs4588 and rs7041 of the vitamin D binding protein (VDBP) have been published so far.

Methods: Serum levels of total 25(OH)D were measured in two general-population samples (total n = 5733) of the Study of Health in Pomerania (SHIP). The Toronto Alexithymia Scale-20 (TAS-20) was applied to measure alexithymia. Study participants were genotyped for rs4588 and rs7041. Linear and logistic regression analyses adjusted for sex, age, waist circumference, physical activity, season and study and, when applicable, for the batch of genotyping and the first three genetic principal components, were performed. In sensitivity analyses, the models were additionally adjusted for depressive symptoms.

Results: 25(OH)D levels were negatively associated with TAS-20 scores (β = -0.002; P < 0.001) and alexithymia according to the common cutoff of TAS-20>60 (β = -0.103; P < 0.001). These results remained stable after adjusting for depressive symptoms. The tested genetic polymorphisms were not significantly associated with alexithymia.

Conclusions: Our results suggest that low vitamin D levels may be involved in the pathophysiology of alexithymia. Given that no associations between alexithymia and rs4588 as well as rs7041 were observed, indicates that behavioral or nutritional features of alexithymic subjects could also explain this association.
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http://dx.doi.org/10.1097/YPG.0000000000000283DOI Listing
August 2021

Association between different dimensions of childhood traumatization and plasma micro-RNA levels in a clinical psychiatric sample.

J Psychiatr Res 2021 07 24;139:113-119. Epub 2021 May 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock, Greifswald, Germany.

As an epigenetic regulator micro-RNAs (miRNAs) have gained increasing attention in biomarker research for diseases. Many studies point towards an involvement of miRNAs in neuropsychiatric disorders such as Alzheimer's Disease, schizophrenia or depression. In a recent study we identified a possible relationship between childhood traumatization and miRNAs associated with Alzheimer's Disease in the general population as well as in a small psychiatric clinical sample. In this study we aimed to confirm this biological link in an independent psychiatric clinical sample (N = 104) and to also explore the impact of different childhood trauma dimensions (sum score, abuse dimension and neglect dimension). Analyses revealed their different impact on disease in the combined sample (N = 154; N = 50 from the recent study). We could confirm associations for all of the four recently identified miRNAs in the replication sample (N = 104) on a suggested significance level of p < 0.08 (two with p < 0.05). In the combined sample (N = 154) fifteen miRNAs were significantly associated with the childhood trauma sum score after correction for multiple testing. Most of them showed recently significant associations for Alzheimer's Disease. For the subscores of abuse and neglect only one miRNA was identified in addition, associated with childhood neglect. Bioinformatics analysis identified significant brain-related pathways regulated by the respective miRNAs. At the time of publication our study is the largest study of the association between childhood trauma and miRNAs in a clinical psychiatric sample. The confirmation of our previous results supports the relevance of the association between childhood traumatization and Alzheimer's Disease through miRNA regulation of brain-related pathways.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.023DOI Listing
July 2021

[Sociodemographic and Disorder-Specific Determinants for Professional Help-seeking due to Depression in a Structurally Weak Region - The Important Role of Age].

Psychiatr Prax 2021 May 20. Epub 2021 May 20.

Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Leipzig.

Objective: Study of sociodemographic and disorder-specific determinants of professional help-seeking in lifetime depression.

Methods: In the population-based SHIP-Trend-1 study (2016-2019), we assessed N = 490 adults with lifetime depression and their help-seeking behaviour. Gender, socioeconomic status and disorder-specific variables were implemented in age-stratified logistic regression models.

Results: Men and older adults at the time of the survey sought less help than women and younger people. In the younger and middle age group severity level was associated with professional help-seeking, in the older age group professional help-seeking was more prevalent in case of physical causes for the depression.

Conclusion: We found age-specific differences in the determinants for professional help-seeking. Latent variables like age-specific experiences, values, and life styles may explain those differences.
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http://dx.doi.org/10.1055/a-1468-3860DOI Listing
May 2021

[Sociodemographic and Disorder-Specific Determinants for Professional Help-seeking due to Depression in a Structurally Weak Region - The Important Role of Age].

Psychiatr Prax 2021 May 20. Epub 2021 May 20.

Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Leipzig.

Objective: Study of sociodemographic and disorder-specific determinants of professional help-seeking in lifetime depression.

Methods: In the population-based SHIP-Trend-1 study (2016-2019), we assessed N = 490 adults with lifetime depression and their help-seeking behaviour. Gender, socioeconomic status and disorder-specific variables were implemented in age-stratified logistic regression models.

Results: Men and older adults at the time of the survey sought less help than women and younger people. In the younger and middle age group severity level was associated with professional help-seeking, in the older age group professional help-seeking was more prevalent in case of physical causes for the depression.

Conclusion: We found age-specific differences in the determinants for professional help-seeking. Latent variables like age-specific experiences, values, and life styles may explain those differences.
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http://dx.doi.org/10.1055/a-1468-3860DOI Listing
May 2021

ENIGMA-Sleep: Challenges, opportunities, and the road map.

J Sleep Res 2021 Apr 28:e13347. Epub 2021 Apr 28.

Department of Sleep and Cognition, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.
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http://dx.doi.org/10.1111/jsr.13347DOI Listing
April 2021

Sex effects for the interaction of dopamine related genetic variants for COMT and BDNF on declarative memory performance.

Genes Brain Behav 2021 Jun 12;20(5):e12737. Epub 2021 May 12.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Genetic factors are assumed to contribute to memory performance, especially genes affecting the dopaminergic neurotransmission. We aimed to evaluate leading functional genetic variants of the dopamine system, Catechol-O-methyltransferase (COMT) SNP rs4680 and Brain-derived neurotropic factor (BDNF) SNP rs6265, previously found to be associated with memory performance. In two independent general population cohorts (total N = 5937) we investigated direct and interaction effects between COMT and BDNF SNPs on declarative memory performance. We found significant two-way interactions for COMT and BDNF in both cohorts but no direct genetic effects. Sensitivity analyses revealed that an interaction between COMT and BDNF was mainly carried by females. While direct associations of COMT and BDNF on memory have been reported previously, we could demonstrate that the interaction of COMT and BDNF is sex-dependent and more complex and needs further investigation. Our results could be demonstrated in two independent cohorts of valuable size.
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http://dx.doi.org/10.1111/gbb.12737DOI Listing
June 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Broad Metabolome Alterations Associated with the Intake of Oral Contraceptives Are Mediated by Cortisol in Premenopausal Women.

Metabolites 2021 Mar 24;11(4). Epub 2021 Mar 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, D-17489 Greifswald, Germany.

The use of oral contraceptives (OCs) has been associated with elevated blood cortisol concentrations. However, metabolic downstream effects of OC intake are not well described. Here, we aimed to determine if the blood metabolome is associated with the use of OCs and to estimate if these associations might be statistically mediated by serum cortisol concentrations. Plasma metabolites measured with the Biocrates Absolute p180 Kit and serum cortisol concentrations measured by an immunoassay were determined in 391 premenopausal women (116 OC users) participating in two independent cohorts of the Study of Health in Pomerania (SHIP). After correction for multiple testing, 27 metabolites were significantly associated with OC intake in SHIP-TREND (discovery cohort), of which 25 replicated in SHIP-2. Inter alia, associated metabolites included 12 out of 38 phosphatidylcholines with diacyl residue, 7 out of 14 lysophosphatidylcholines and 5 out of 21 amino acids. The associations with phosphatidylcholines were statistically mediated by cortisol, whereas lysophosphatidylcholines showed no mediation effect. The results represent a step toward a better understanding of the metabolic consequences of OC intake. Connecting cortisol with metabolic consequences of OC intake could help to understand the mechanisms underlying adverse effects. The blood metabolome may serve as a biomarker for identifying users at high risk for developing such adverse effects.
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http://dx.doi.org/10.3390/metabo11040193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064380PMC
March 2021

Genetic factors influencing a neurobiological substrate for psychiatric disorders.

Transl Psychiatry 2021 03 29;11(1):192. Epub 2021 Mar 29.

Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Jülich, Germany.

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex-areas that constitute hub nodes of the salience network-represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.
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http://dx.doi.org/10.1038/s41398-021-01317-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007575PMC
March 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

The genetic predisposition to longevity acts through behavioral phenotypes in females.

Eur Neuropsychopharmacol 2021 Apr 14;45:1-14. Epub 2021 Mar 14.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ellernholzstraße 1-2, 17475 Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Germany.

The discovery of genetic factors for the predisposition of longevity is promising but their functional role and clinical relevance remain largely unclear. Based on results from a large genome-wide association study (GWAS) on human longevity (N ≈ 390,000) we identified six phenotype categories belonging to behavioral and psychiatric traits showing significant genetic correlations using LD Hub. We validated these genetic correlations on the phenotype level in a general population sample using a polygenic risk score (PRS) based on the longevity GWAS as proxy for longevity (N ≈ 8190; Study of Health in Pomerania). The behavioral phenotypes education, smoking and body mass index (BMI) were highly associated with the PRS for longevity especially in females (p=0.003, p=0.049, p=2.0E-4) with increased rates for higher education, lower smoking rates and decrease in BMI attributed to a higher PRS for longevity. Moreover, the psychiatric phenotypes depression and subjective health complaints showed significant associations (p=0.032, p=0.002) in females only. Generally, a higher genetic predisposition for longevity had a stronger association with behavioral phenotypes in females than in males. It is unclear what causes the higher ``behavioral heterogeneity'' in males but different biological mechanisms might be involved. Sensitivity analyses showed that the association for the PRS for longevity with BMI and smoking were robust against adjustment with the PRS for BMI and smoking. In conclusion, our analyses demonstrated that genetic information obtained from highly powered GWAS for longevity revealed a clear behavioral signature on the phenotype level in a smaller population based sample.
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http://dx.doi.org/10.1016/j.euroneuro.2021.02.014DOI Listing
April 2021

The association between genetically determined ABO blood types and major depressive disorder.

Psychiatry Res 2021 05 24;299:113837. Epub 2021 Feb 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.

ABO blood types and their corresponding antigens have long been assumed to be related to different human diseases. So far, smaller studies on the relationship between mental disorders and blood types yielded contradicting results. In this study we analyzed the association between ABO blood types and lifetime major depressive disorder (MDD). We performed a pooled analysis with data from 26 cohorts that are part of the MDD working group of the Psychiatric Genomics Consortium (PGC). The dataset included 37,208 individuals of largely European ancestry of which 41.6% were diagnosed with lifetime MDD. ABO blood types were identified using three single nucleotide polymorphisms in the ABO gene: rs505922, rs8176746 and rs8176747. Regression analyses were performed to assess associations between the individual ABO blood types and MDD diagnosis as well as putative interaction effects with sex. The models were adjusted for sex, cohort and the first ten genetic principal components. The percentage of blood type A was slightly lower in cases than controls while blood type O was more prominent in cases. However, these differences were not statistically significant. Our analyses found no evidence of an association between ABO blood types and major depressive disorder.
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http://dx.doi.org/10.1016/j.psychres.2021.113837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071927PMC
May 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
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http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

Similarities and Differences of Mental Health in Women and Men: A Systematic Review of Findings in Three Large German Cohorts.

Front Public Health 2021 5;9:553071. Epub 2021 Feb 5.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.

In Germany, large, population-based cohort studies have been implemented in order to identify risk and protective factors for maintaining health across the life span. The purpose of this systematic review is to analyse findings from three large ongoing cohorts and to identify sex-specific prevalence rates, risk and protective factors for mental health. Published studies from the Cooperative Health Research in the Region Augsburg (KORA), the Study of Health in Pomerania (SHIP) and the Gutenberg Health Study (GHS)), representing the southern, north-eastern and middle parts of Germany, were identified through searches of the databases PubMed and Web of Science. A total of 52 articles was identified from the start of each cohort until June 2019. Articles reporting prevalence rates of mental health [ = 22], explanatory factors for mental health [ = 25], or both [ = 5] were identified. Consistent across cohorts, higher prevalence rates of internalizing disorders were found for women and more externalizing disorders for men. Risk and protective factors for mental health included social factors, lifestyle, physical health, body mass index (BMI), diabetes, genetic and biological factors. In all areas, differences and similarities were found between women and men. The most evident were the sex-specific risk profiles for depression with mostly external risk factors for men and internal risk factors for women. Gender was not assessed directly, therefore we examined whether socioeconomic and family-related factors reflecting gender roles or institutionalized gender could be used as a proxy for gender. Overall, this systematic review shows differences and similarities in prevalence rates and determinants of mental health indicators between women and men. They underline the importance of focussing on sex specific approaches in mental health research and in the development of prevention measures. Current research on mental health still lacks focus on gender aspects. Therefore, an increased focus on sex and gender in mental health research is of great importance.
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http://dx.doi.org/10.3389/fpubh.2021.553071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892592PMC
May 2021

From heterogeneous healthcare data to disease-specific biomarker networks: A hierarchical Bayesian network approach.

PLoS Comput Biol 2021 02 12;17(2):e1008735. Epub 2021 Feb 12.

Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany.

In this work, we introduce an entirely data-driven and automated approach to reveal disease-associated biomarker and risk factor networks from heterogeneous and high-dimensional healthcare data. Our workflow is based on Bayesian networks, which are a popular tool for analyzing the interplay of biomarkers. Usually, data require extensive manual preprocessing and dimension reduction to allow for effective learning of Bayesian networks. For heterogeneous data, this preprocessing is hard to automatize and typically requires domain-specific prior knowledge. We here combine Bayesian network learning with hierarchical variable clustering in order to detect groups of similar features and learn interactions between them entirely automated. We present an optimization algorithm for the adaptive refinement of such group Bayesian networks to account for a specific target variable, like a disease. The combination of Bayesian networks, clustering, and refinement yields low-dimensional but disease-specific interaction networks. These networks provide easily interpretable, yet accurate models of biomarker interdependencies. We test our method extensively on simulated data, as well as on data from the Study of Health in Pomerania (SHIP-TREND), and demonstrate its effectiveness using non-alcoholic fatty liver disease and hypertension as examples. We show that the group network models outperform available biomarker scores, while at the same time, they provide an easily interpretable interaction network.
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http://dx.doi.org/10.1371/journal.pcbi.1008735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906470PMC
February 2021

Associations and interactions of the serotonin receptor genes 5-HT1A, 5-HT2A, and childhood trauma with alexithymia in two independent general-population samples.

Psychiatry Res 2021 04 3;298:113783. Epub 2021 Feb 3.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Center for Neurodegenerative Diseases DZNE, Site Rostock/ Greifswald, Germany.

Previous studies suggested that childhood trauma and a disturbed serotonergic neurotransmission are involved in the pathogenesis of alexithymia. Specifically, genetic polymorphisms of the serotonin receptors 5-HT1A and 5-HT2A were found to be associated with alexithymia. However, it is unclear whether these factors show main or interaction effects with childhood trauma on alexithymia. Data from two independent general-population cohorts of the Study of Health in Pomerania (SHIP-Trend: N=3,706, Age: range=20-83, 51.6% female, SHIP-LEGEND: N=2,162, Age: range=20-80, 52.5% female) were used. The Toronto Alexithymia Scale-20 (TAS-20) and the Childhood Trauma Questionnaire (CTQ) were applied. Genotypes of rs6295 of 5-HT1A and rs6311 of 5-HT2A were determined. Ordinary least-squared regression models with robust standard errors were applied to investigate associations of the main and interaction effects of childhood maltreatment and the polymorphisms with alexithymia. Childhood trauma, but none of the investigated polymorphisms showed main effects on alexithymia. However, childhood trauma showed significant CTQ sum score x rs6295 interactions in male subjects in both samples such that the presence of the G-allele diminished the CTQ associated increase in the TAS-20 sum scores. Our results support a strong role of early life stress and interactions with rs6295 on alexithymic personality features at least in male subjects.
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http://dx.doi.org/10.1016/j.psychres.2021.113783DOI Listing
April 2021

Alexithymia is associated with increased all-cause mortality risk in men, but not in women: A 10-year follow-up study.

J Psychosom Res 2021 04 27;143:110372. Epub 2021 Jan 27.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ellernholzstraße 1-2, 17475 Greifswald, Germany; German Center for Neurodegenerative Diseases DZNE, Site Rostock/Greifswald, Ellernholzstraße 1-2, 17475 Greifswald, Germany.

Objective: Alexithymia is associated with various mental as well as physical disorders. Some evidence also suggested high alexithymia to increase mortality risk, but these results are few and based on specific sample compositions. We aimed to investigate the impact of alexithymia on mortality risk in a large population based cohort. In addition, we sought to elucidate the effects of the subfactors of alexithymia and sex differences.

Methods: In a sample of N = 1380 individuals from the Study of Health in Pomerania (SHIP), we investigated the hazard-ratio (HR) of alexithymia as obtained by the Toronto Alexithymia Scale-20 (TAS-20) on all-cause mortality over an average observation time of 10 years. Sex-by-TAS-20-interactions as well as sex-stratified analyses were performed.

Results: Alexithymia was significantly associated with enhanced mortality risk (HR = 1.033; 95%-CI = 1.008-1.058); p = 0.009). While sex-by-TAS-20 interactions remained insignificant, sex-stratified analyses showed that this effect was only significant in men (HR = 1.050; 95%-CI = 1.022-1.079; p ≤ 0.001), but not in women (HR: 1.008; 95%-CI = 0.960-1.057; p = 0.76). The effect was validated for the "difficulties identifying feelings" (DIF) and "difficulties describing feelings" (DDF) subfactors of the TAS-20.

Conclusion: Our study supports and extents previous findings by indicating that mortality risk enhancing effects of alexithymia are specific to male subjects and validated for the DIF and DDF facets. Socioeconomic, clinical and metabolic factors were associated with this relationship. Finding that the impact of alexithymia remains stable in the fully adjusted models suggests that yet unidentified additional factors must be considered.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110372DOI Listing
April 2021

Associated factors of white matter hyperintensity volume: a machine-learning approach.

Sci Rep 2021 01 27;11(1):2325. Epub 2021 Jan 27.

Department of Radiology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.

To identify the most important parameters associated with cerebral white matter hyperintensities (WMH), in consideration of potential collinearity, we used a data-driven machine-learning approach. We analysed two independent cohorts (KORA and SHIP). WMH volumes were derived from cMRI-images (FLAIR). 90 (KORA) and 34 (SHIP) potential determinants of WMH including measures of diabetes, blood-pressure, medication-intake, sociodemographics, life-style factors, somatic/depressive-symptoms and sleep were collected. Elastic net regression was used to identify relevant predictor covariates associated with WMH volume. The ten most frequently selected variables in KORA were subsequently examined for robustness in SHIP. The final KORA sample consisted of 370 participants (58% male; age 55.7 ± 9.1 years), the SHIP sample comprised 854 participants (38% male; age 53.9 ± 9.3 years). The most often selected and highly replicable parameters associated with WMH volume were in descending order age, hypertension, components of the social environment (i.e. widowed, living alone) and prediabetes. A systematic machine-learning based analysis of two independent, population-based cohorts showed, that besides age and hypertension, prediabetes and components of the social environment might play important roles in the development of WMH. Our results enable personal risk assessment for the development of WMH and inform prevention strategies tailored to the individual patient.
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http://dx.doi.org/10.1038/s41598-021-81883-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840689PMC
January 2021

Childhood maltreatment and lung function: findings from the general population.

Eur Respir J 2021 04 8;57(4). Epub 2021 Apr 8.

Dept of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Objective: Cumulative evidence indicates that childhood maltreatment is linked to self-reported asthma and COPD. However, the relationship between childhood maltreatment and objective measures of lung function as determined by spirometry has not yet been assessed.

Methods: Medical histories and spirometric lung function were taken in 1386 adults from the general population. Participants completed the Childhood Trauma Questionnaire for the assessment of emotional, physical and sexual abuse as well as emotional and physical neglect.

Results: 25.3% of the participants reported at least one type of childhood maltreatment. Among them, use of medication for obstructive airway diseases as well as typical signs and symptoms of airflow limitation were significantly more frequent than in the group without exposure to childhood maltreatment. Although participants with childhood maltreatment had numerically lower values for forced expiratory volume in 1 s (FEV), forced vital capacity (FVC) and peak expiratory flow than those without, these differences were nonsignificant when accounting for relevant covariates such as age, sex, height and smoking. Likewise, there were no differences in the FEV/FVC ratio nor in the frequency of airflow limitation regardless of its definition. No specific type of childhood maltreatment was related to spirometrically determined parameters of lung function.

Conclusions: Our findings call into question the association of childhood maltreatment with obstructive lung diseases as indicated by prior research relying on self-reported diagnoses. We consider several explanations for these discrepancies.
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http://dx.doi.org/10.1183/13993003.02882-2020DOI Listing
April 2021

The genetics of circulating BDNF: towards understanding the role of BDNF in brain structure and function in middle and old ages.

Brain Commun 2020 28;2(2):fcaa176. Epub 2020 Oct 28.

Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, 78229 TX, USA.

Brain-derived neurotrophic factor (BDNF) plays an important role in brain development and function. Substantial amounts of BDNF are present in peripheral blood, and may serve as biomarkers for Alzheimer's disease incidence as well as targets for intervention to reduce Alzheimer's disease risk. With the exception of the genetic polymorphism in the gene, Val66Met, which has been extensively studied with regard to neurodegenerative diseases, the genetic variation that influences circulating BDNF levels is unknown. We aimed to explore the genetic determinants of circulating BDNF levels in order to clarify its mechanistic involvement in brain structure and function and Alzheimer's disease pathophysiology in middle-aged and old adults. Thus, we conducted a meta-analysis of genome-wide association study of circulating BDNF in 11 785 middle- and old-aged individuals of European ancestry from the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES), the Framingham Heart Study (FHS), the Rotterdam Study and the Study of Health in Pomerania (SHIP-Trend). Furthermore, we performed functional annotation analysis and related the genetic polymorphism influencing circulating BDNF to common Alzheimer's disease pathologies from brain autopsies. Mendelian randomization was conducted to examine the possible causal role of circulating BDNF levels with various phenotypes including cognitive function, stroke, diabetes, cardiovascular disease, physical activity and diet patterns. Gene interaction networks analysis was also performed. The estimated heritability of BDNF levels was 30% (standard error = 0.0246, -value = 4 × 10). We identified seven novel independent loci mapped near the gene and in , , , (two single-nucleotide polymorphisms) and . The expression of was associated with neurofibrillary tangles in brain tissues from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Seven additional genes (, , , , , and ) were identified through expression and protein quantitative trait loci analyses. Mendelian randomization analyses indicated a potential causal role of BDNF in cardioembolism. Lastly, Ingenuity Pathway Analysis placed circulating BDNF levels in four major networks. Our study provides novel insights into genes and molecular pathways associated with circulating BDNF levels and highlights the possible involvement of plaque instability as an underlying mechanism linking BDNF with brain neurodegeneration. These findings provide a foundation for a better understanding of BDNF regulation and function in the context of brain aging and neurodegenerative pathophysiology.
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http://dx.doi.org/10.1093/braincomms/fcaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734441PMC
October 2020
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