Publications by authors named "Jessika Sussmann"

38 Publications

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

Diffusion tensor imaging correlates of early markers of depression in youth at high-familial risk for bipolar disorder.

J Child Psychol Psychiatry 2018 08 28;59(8):917-927. Epub 2018 Feb 28.

Division of Psychiatry, University of Edinburgh, Edinburgh, UK.

Background: Mood disorders are familial psychiatric diseases, in which patients show reduced white matter (WM) integrity. We sought to determine whether WM integrity was affected in young offspring at high-familial risk of mood disorder before they go on to develop major depressive disorder (MDD).

Methods: The Bipolar Family study is a prospective longitudinal study examining young individuals (age 16-25 years) at familial risk of mood disorder on three occasions 2 years apart. This study used baseline imaging data, categorizing groups according to clinical outcome at follow-up. Diffusion tensor MRI data were acquired for 61 controls and 106 high-risk individuals, the latter divided into 78 high-risk subjects who remained well throughout the study ('high-risk well') and 28 individuals who subsequently developed MDD ('high-risk MDD'). Voxel-wise between-group comparison of fractional anisotropy (FA) based on diagnostic status was performed using tract-based spatial statistics (TBSS).

Results: Compared to controls, both high-risk groups showed widespread decreases in FA (p  < .05) at baseline. Although FA in the high-risk MDD group negatively correlated with subthreshold depressive symptoms at the time of scanning (p  < .05), there were no statistically significant differences at p-corrected levels between the two high-risk groups.

Conclusions: These results suggest that decreased FA is related to the presence of familial risk for mood disorder along with subdiagnostic symptoms at the time of scanning rather than predictive of subsequent diagnosis. Due to the difficulties performing such longitudinal prospective studies, we note, however, that this latter analysis may be underpowered due to sample size within the high-risk MDD group. Further clinical follow-up may clarify these findings.
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http://dx.doi.org/10.1111/jcpp.12879DOI Listing
August 2018

Longitudinal differences in white matter integrity in youth at high familial risk for bipolar disorder.

Bipolar Disord 2017 05 3;19(3):158-167. Epub 2017 May 3.

Institut universitaire en santé mentale de Québec, Québec City, Québec, Canada.

Objectives: Previous neuroimaging studies have reported abnormalities in white matter (WM) pathways in subjects at high familial risk of mood disorders. In the current study, we examined the trajectory of these abnormalities during the early stages of illness development using longitudinal diffusion tensor imaging (DTI) data.

Methods: Subjects (16-28 years old) were recruited in the Scottish Bipolar Family Study, a prospective longitudinal study that has examined individuals at familial risk of mood disorder on three occasions, 2 years apart. The current study concerns imaging data from the first and second assessments. We analysed DTI data for 43 controls and 69 high-risk individuals who were further subdivided into a group of 53 high-risk subjects who remained well (high-risk well) and 16 who met diagnostic criteria for major depressive disorder (high-risk MDD) at follow-up. Longitudinal differences in fractional anisotropy (FA) between groups based on diagnostic status were investigated using the tract-based spatial statistics technique (TBSS).

Results: We found a significant reduction in FA (P <.05) across widespread brain regions over 2 years in all three groups. The trajectory of FA reduction did not differ significantly between groups.

Conclusions: These results suggest that there are similar trajectories of FA reductions for controls and high-risk young adults, despite high-risk individuals being at a disadvantaged starting point considering their reduced WM integrity detected at baseline in previous studies. Difference in WM integrity between high-risk individuals and controls could therefore occur in earlier childhood and be a necessary but not sufficient condition to develop future mood disorders.
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http://dx.doi.org/10.1111/bdi.12489DOI Listing
May 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

Deactivation in anterior cingulate cortex during facial processing in young individuals with high familial risk and early development of depression: fMRI findings from the Scottish Bipolar Family Study.

J Child Psychol Psychiatry 2016 11 15;57(11):1277-1286. Epub 2016 Jul 15.

Division of Psychiatry, University of Edinburgh, Edinburgh, UK.

Background: Studies have identified perturbations in facial processing in bipolar disorder and major depressive disorder (MDD), but their relationship to genetic risk and early development of illness is unclear.

Methods: The Scottish Bipolar Family Study is a prospective longitudinal investigation examining young individuals (age 16-25) at familial risk of mood disorder. Participants underwent functional MRI using an implicit facial processing task employing angry and neutral faces. An explicit facial expression recognition task was completed outside the scanner. Clinical outcomes obtained 2 years after the scan were used to categorise participants into controls (n = 54), high-risk individuals who had developed MDD (HR MDD; n = 30) and high-risk individuals who remained well (HR Well, n = 43).

Results: All groups demonstrated activation patterns typically observed during facial processing, including activation of the amygdala, hippocampus, fusiform gyrus and middle frontal regions. Notably, the HR MDD group showed reduced activation of the anterior cingulate gyrus versus both the control and HR Well group for angry faces, and versus the HR Well group for neutral faces. Outside the scanner, the HR MDD group was less accurate in recognising fearful expressions than the HR Well group.

Conclusions: Here, we demonstrate functional abnormalities of the anterior cingulate cortex alongside facial emotional recognition deficits in high-risk individuals in the early stages of depression compared with both controls and at-risk individuals who remained well. These neural changes were associated with a current or future diagnosis of MDD and were not simply associated with increased familial risk.
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http://dx.doi.org/10.1111/jcpp.12591DOI Listing
November 2016

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

Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders.

Bipolar Disord 2016 08 21;18(5):410-22. Epub 2016 Jul 21.

Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK.

Objectives: Accumulating evidence implicates altered DNA methylation in psychiatric disorders, including bipolar disorder (BD) and major depressive disorder (MDD). It is not clear, however, whether these changes are causative or result from illness progression or treatment. To disentangle these possibilities we profiled genome-wide DNA methylation in well, unrelated individuals at high familial risk of mood disorder. DNA methylation was compared between individuals who subsequently developed BD or MDD [ill later (IL)] and those who remained well [well later (WL)].

Methods: DNA methylation profiles were obtained from whole-blood samples from 22 IL and 23 WL individuals using the Infinium HumanMethylation450 BeadChip. Differential methylation was assessed on a single-locus and regional basis. Pathway analysis was performed to assess enrichment for particular biological processes amongst nominally significantly differentially methylated loci.

Results: Although no locus withstood correction for multiple testing, uncorrected P-values provided suggestive evidence for altered methylation at sites within genes previously implicated in neuropsychiatric conditions, such as Transcription Factor 4 (TCF4) and Interleukin 1 Receptor Accessory Protein-Like 1 ([IL1RAPL1]; P≤3.11×10(-5) ). Pathway analysis revealed significant enrichment for several neurologically relevant pathways and functions, including Nervous System Development and Function and Behavior; these findings withstood multiple testing correction (q≤0.05). Analysis of differentially methylated regions identified several within the major histocompatibility complex (P≤.000 479), a region previously implicated in schizophrenia and BD.

Conclusions: Our data provide provisional evidence for the involvement of altered whole-blood DNA methylation in neurologically relevant genes in the aetiology of mood disorders. These findings are convergent with the findings of genome-wide association studies.
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http://dx.doi.org/10.1111/bdi.12415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006843PMC
August 2016

DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.

Clin Epigenetics 2016 20;8. Epub 2016 Jan 20.

Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK ; Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ UK.

Background: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI.

Results: Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes.

Conclusions: Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation.
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http://dx.doi.org/10.1186/s13148-016-0171-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721115PMC
April 2016

Prospective longitudinal study of subcortical brain volumes in individuals at high familial risk of mood disorders with or without subsequent onset of depression.

Psychiatry Res Neuroimaging 2016 Feb 31;248:119-25. Epub 2015 Dec 31.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, United Kingdom.

Subcortical volumetric brain abnormalities have been observed in mood disorders. However, it is unknown whether these reflect adverse effects predisposing to mood disorders or emerge at illness onset. Magnetic resonance imaging was conducted at baseline and after two years in 111 initially unaffected young adults at increased risk of mood disorders because of a close family history of bipolar disorder and 93 healthy controls (HC). During the follow-up, 20 high-risk subjects developed major depressive disorder (HR-MDD), with the others remaining well (HR-well). Volumes of the lateral ventricles, caudate, putamen, pallidum, thalamus, hippocampus and amygdala were extracted for each hemisphere. Using linear mixed-effects models, differences and longitudinal changes in subcortical volumes were investigated between groups (HC, HR-MDD, HR-well). There were no significant differences for any subcortical volume between groups controlling for multiple testing. Additionally, no significant differences emerged between groups over time. Our results indicate that volumetric subcortical brain abnormalities of these regions using the current method appear not to form familial trait markers for vulnerability to mood disorders in close relatives of bipolar disorder patients over the two-year time period studied. Moreover, they do not appear to reduce in response to illness onset at least for the time period studied.
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http://dx.doi.org/10.1016/j.pscychresns.2015.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834463PMC
February 2016

Heritability of fractional anisotropy in human white matter: a comparison of Human Connectome Project and ENIGMA-DTI data.

Neuroimage 2015 May 4;111:300-11. Epub 2015 Mar 4.

University of Texas Health Science Center San Antonio, San Antonio, TX, USA.

The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed by state-of-the-art neuroimaging methods. We calculated the heritability of the fractional anisotropy (FA) measure derived from diffusion tensor imaging (DTI) reconstruction in 481 HCP subjects (194/287 M/F) consisting of 57/60 pairs of mono- and dizygotic twins, and 246 siblings. FA measurements were derived using (Enhancing NeuroImaging Genetics through Meta-Analysis) ENIGMA DTI protocols and heritability estimates were calculated using the SOLAR-Eclipse imaging genetic analysis package. We compared heritability estimates derived from HCP data to those publicly available through the ENIGMA-DTI consortium, which were pooled together from five-family based studies across the US, Europe, and Australia. FA measurements from the HCP cohort for eleven major white matter tracts were highly heritable (h(2)=0.53-0.90, p<10(-5)), and were significantly correlated with the joint-analytical estimates from the ENIGMA cohort on the tract and voxel-wise levels. The similarity in regional heritability suggests that the additive genetic contribution to white matter microstructure is consistent across populations and imaging acquisition parameters. It also suggests that the overarching genetic influence provides an opportunity to define a common genetic search space for future gene-discovery studies. Uniquely, the measurements of additive genetic contribution performed in this study can be repeated using online genetic analysis tools provided by the HCP ConnectomeDB web application.
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http://dx.doi.org/10.1016/j.neuroimage.2015.02.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387079PMC
May 2015

Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder.

J Psychiatr Res 2015 Mar 22;62:48-55. Epub 2015 Jan 22.

Medical Genetics Section, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. Electronic address:

Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD.
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http://dx.doi.org/10.1016/j.jpsychires.2015.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379383PMC
March 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

Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk.

Schizophr Res 2015 Feb 20;161(2-3):484-9. Epub 2014 Nov 20.

Division of Psychiatry, University of Edinburgh, Edinburgh, UK.

Evidence suggests that there is shared genetic aetiology across the major psychiatric disorders conferred by additive effects of many common variants. Measuring their joint effects on brain function may identify common neural risk mechanisms. We investigated the effects of a cross-disorder polygenic risk score (PGRS), based on additive effects of genetic susceptibility to the five major psychiatric disorders, on brain activation during performance of a language-based executive task. We examined this relationship in healthy individuals with (n=82) and without (n=57) a family history of bipolar disorder to determine whether this effect was additive or interactive dependent on the presence of family history. We demonstrate a significant interaction for polygenic loading×group in left lateral frontal cortex (BA9, BA6). Further examination indicated that this was driven by a significant positive correlation in those without a family history (i.e. healthy unrelated volunteers), with no significant relationships in the familial group. We then examined the effect of the individual diagnoses contributing to the PGRS to determine evidence of disorder-specificity. We found a significant association with the schizophrenia polygenic score only, with no other significant relationships. These findings indicate differences in left lateral frontal brain activation in association with increased cross-disorder PGRS in individuals without a family history of psychiatric illness. Lack of effects in the familial group may reflect epistatic effects, shared environmental influences or effects not captured by the PGRS. The specific relationship with loading for schizophrenia is notably consistent with frontal cortical inefficiency as a circumscribed phenotype of psychotic disorders.
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http://dx.doi.org/10.1016/j.schres.2014.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396692PMC
February 2015

Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling.

Neuroimage 2014 Jul 18;95:136-50. Epub 2014 Mar 18.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.
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http://dx.doi.org/10.1016/j.neuroimage.2014.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043878PMC
July 2014

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.

Brain Imaging Behav 2014 Jun;8(2):153-82

Imaging Genetics Center, Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, 2001 N. Soto Street, Los Angeles, CA, 90033, USA,

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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http://dx.doi.org/10.1007/s11682-013-9269-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008818PMC
June 2014

A genome-wide association analysis of a broad psychosis phenotype identifies three loci for further investigation.

Biol Psychiatry 2014 Mar 17;75(5):386-97. Epub 2013 Jul 17.

Background: Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories.

Methods: 1239 cases with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder; 857 of their unaffected relatives, and 2739 healthy controls were genotyped with the Affymetrix 6.0 single nucleotide polymorphism (SNP) array. Analyses of 695,193 SNPs were conducted using UNPHASED, which combines information across families and unrelated individuals. We attempted to replicate signals found in 23 genomic regions using existing data on nonoverlapping samples from the Psychiatric GWAS Consortium and Schizophrenia-GENE-plus cohorts (10,352 schizophrenia patients and 24,474 controls).

Results: No individual SNP showed compelling evidence for association with psychosis in our data. However, we observed a trend for association with same risk alleles at loci previously associated with schizophrenia (one-sided p = .003). A polygenic score analysis found that the Psychiatric GWAS Consortium's panel of SNPs associated with schizophrenia significantly predicted disease status in our sample (p = 5 × 10(-14)) and explained approximately 2% of the phenotypic variance.

Conclusions: Although narrowly defined phenotypes have their advantages, we believe new loci may also be discovered through meta-analysis across broad phenotypes. The novel statistical methodology we introduced to model effect size heterogeneity between studies should help future GWAS that combine association evidence from related phenotypes. Applying these approaches, we highlight three loci that warrant further investigation. We found that SNPs conveying risk for schizophrenia are also predictive of disease status in our data.
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http://dx.doi.org/10.1016/j.biopsych.2013.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923972PMC
March 2014

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA-DTI working group.

Neuroimage 2013 Nov 28;81:455-469. Epub 2013 Apr 28.

Imaging Genetics Center, Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, CA, USA. Electronic address:

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA-DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18-85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/).
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http://dx.doi.org/10.1016/j.neuroimage.2013.04.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729717PMC
November 2013

Prediction of depression in individuals at high familial risk of mood disorders using functional magnetic resonance imaging.

PLoS One 2013 6;8(3):e57357. Epub 2013 Mar 6.

Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.

Objective: Bipolar disorder is a highly heritable condition. First-degree relatives of affected individuals have a more than a ten-fold increased risk of developing bipolar disorder (BD), and a three-fold risk of developing major depressive disorder (MDD) than the general population. It is unclear however whether differences in brain activation reported in BD and MDD are present before the onset of illness.

Methods: We studied 98 young unaffected individuals at high familial risk of BD and 58 healthy controls using functional Magnetic Resonance Imaging (fMRI) scans and a task involving executive and language processing. Twenty of the high-risk subjects subsequently developed MDD after the baseline fMRI scan.

Results: At baseline the high-risk subjects who later developed MDD demonstrated relatively increased activation in the insula cortex, compared to controls and high risk subjects who remained well. In the healthy controls and high-risk group who remained well, this region demonstrated reduced engagement with increasing task difficulty. The high risk subjects who subsequently developed MDD did not demonstrate this normal disengagement. Activation in this region correlated positively with measures of cyclothymia and neuroticism at baseline, but not with measures of depression.

Conclusions: These results suggest that increased activation of the insula can differentiate individuals at high-risk of bipolar disorder who later develop MDD from healthy controls and those at familial risk who remain well. These findings offer the potential of future risk stratification in individuals at risk of mood disorder for familial reasons.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057357PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590244PMC
September 2013

Polygenic risk and white matter integrity in individuals at high risk of mood disorder.

Biol Psychiatry 2013 Aug 28;74(4):280-6. Epub 2013 Feb 28.

Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.

Background: Bipolar disorder (BD) and major depressive disorder (MDD) are highly heritable and genetically overlapping conditions characterized by episodic elevation and/or depression of mood. Both demonstrate abnormalities in white matter integrity, measured with diffusion tensor magnetic resonance imaging, that are also heritable. However, it is unclear how these abnormalities relate to the underlying genetic architecture of each disorder. Genome-wide association studies have demonstrated a significant polygenic contribution to BD and MDD, where risk is attributed to the summation of many alleles of small effect. Determining the effects of an overall polygenic risk profile score on neuroimaging abnormalities might help to identify proxy measures of genetic susceptibility and thereby inform models of risk prediction.

Methods: In the current study, we determined the extent to which common genetic variation underlying risk to mood disorders (BD and MDD) was related to fractional anisotropy, an index of white matter integrity. This was conducted in unaffected individuals at familial risk of mood disorder (n = 70) and comparison subjects (n = 62). Polygenic risk scores were calculated separately for BD and MDD on the basis of genome-wide association study data from the Psychiatric GWAS Consortia.

Results: We report that a higher polygenic risk allele load for MDD was significantly associated with decreased white matter integrity across both groups in a large cluster, with a peak in the right-sided superior longitudinal fasciculus.

Conclusions: These findings suggest that the polygenic approach to examining brain imaging data might be a useful means of identifying traits linked to the genetic risk of mood disorders.
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http://dx.doi.org/10.1016/j.biopsych.2013.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185278PMC
August 2013

Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.

Neuropsychopharmacology 2012 Nov 1;37(12):2720-9. Epub 2012 Aug 1.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

A recent 'mega-analysis' combining genome-wide association study data from over 40,000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as 'RISK-' for GT and GG individuals, and 'RISK+' for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK- individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype(*)group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK- genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ.
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http://dx.doi.org/10.1038/npp.2012.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473338PMC
November 2012

Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia.

Bipolar Disord 2012 Jun;14(4):411-31

Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK.

Objective: Although bipolar disorder (BD) and schizophrenia (SCZ) have a number of clinical features and certain susceptibility genes in common, they are considered separate disorders, and it is unclear which aspects of pathophysiology are specific to each condition. Here, we examine the functional magnetic resonance imaging (fMRI) literature to determine the evidence for diagnosis-specific patterns of brain activation in the two patient groups.

Method: A systematic search was performed to identify fMRI studies directly comparing BD and SCZ to examine evidence for diagnosis-specific activation patterns. Studies were categorized into (i) those investigating emotion, reward, or memory, (ii) those describing executive function or language tasks, and (iii) those looking at the resting state or default mode networks. Studies reporting estimates of sensitivity and specificity of classification are also summarized, followed by studies reporting associations with symptom severity measures.

Results: In total, 21 studies were identified including patients (n = 729) and healthy subjects (n = 465). Relative over-activation in the medial temporal lobe and associated structures was found in BD versus SCZ in tasks involving emotion or memory. Evidence of differences between the disorders in prefrontal regions was less consistent. Accuracy values for assignment of diagnosis were generally lower in BD than in SCZ. Few studies reported significant symptom associations; however, these generally implicated limbic regions in association with manic symptoms.

Conclusions: Although there are a limited number of studies and a cautious approach is warranted, activation differences were found in the medial temporal lobe and associated limbic regions, suggesting the presence of differences in the neurobiological substrates of SCZ and BD. Future studies examining symptom dimensions, risk-associated genes, and the effects of medication will aid clarification of the mechanisms behind these differences.
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http://dx.doi.org/10.1111/j.1399-5618.2012.01016.xDOI Listing
June 2012

Identification of common variants associated with human hippocampal and intracranial volumes.

Nat Genet 2012 Apr 15;44(5):552-61. Epub 2012 Apr 15.

Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).
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http://dx.doi.org/10.1038/ng.2250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635491PMC
April 2012

Effects of a mis-sense DISC1 variant on brain activation in two cohorts at high risk of bipolar disorder or schizophrenia.

Am J Med Genet B Neuropsychiatr Genet 2012 Apr 15;159B(3):343-53. Epub 2012 Feb 15.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

Bipolar disorder and schizophrenia share a number of clinical features and genetic risk variants of small effect, suggesting overlapping pathogenic mechanisms. The effect of single genetic risk variants on brain function is likely to differ in people at high familial risk versus controls as these individuals have a higher overall genetic loading and are therefore closer to crossing a threshold of disease liability. Therefore, whilst the effects of genetic risk variants on brain function may be similar across individuals at risk of both disorders, they are hypothesized to differ compared to that seen in control subjects. We sought to examine the effects of the DISC1 Leu(607) Phe polymorphism on brain activation in young healthy individuals at familial risk of bipolar disorder (n = 84), in a group of controls (n = 78), and in a group at familial risk of schizophrenia (n = 47), performing a language task. We assessed whether genotype effects on brain activation differed according to risk status. There was a significant genotype × group interaction in a cluster centered on the left pre/postcentral gyrus, extending to the inferior frontal gyrus. The origin of this genotype × group effect originated from a significant effect of the presumed risk variant (Phe) on brain activation in the control group, which was absent in both high-risk groups. Differential effects of this polymorphism in controls compared to the two familial groups suggests a commonality of effect across individuals at high-risk of the disorders, which is likely to be dependant upon existing genetic background.
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http://dx.doi.org/10.1002/ajmg.b.32035DOI Listing
April 2012

Effect of variation in diacylglycerol kinase η (DGKH) gene on brain function in a cohort at familial risk of bipolar disorder.

Neuropsychopharmacology 2012 Mar 2;37(4):919-28. Epub 2011 Nov 2.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

Several lines of evidence indicate that the diacylglycerol kinase eta (DGKH) gene is implicated in the etiology of bipolar disorder (BD). However, the functional neural mechanisms of DGKH's risk association remain unknown. Therefore, we examined the effects of three haplotype-tagging risk variants in DGKH (single nucleotide polymorphisms rs9315885, rs1012053, and rs1170191) on brain activation using a verbal fluency functional magnetic resonance imaging task. The subject groups consisted of young individuals at high familial risk of BD (n=81) and a comparison group of healthy controls (n=75). Individuals were grouped based on risk haplotypes described in previous studies. There was a significant risk haplotype*group interaction in the left medial frontal gyrus (BA10, involving anterior cingulate BA32), left precuneus, and right parahippocampal gyrus. All regions demonstrated greater activation during the baseline condition than sentence completion. Individuals at high familial risk for BD homozygous for the DGKH risk haplotype demonstrated relatively greater activation (poor suppression) of these regions during the task vs the low-risk haplotype subjects. The reverse pattern was seen for the control subjects. These findings suggest that there are differential effects of the DGKH gene in healthy controls vs the bipolar high-risk group, which manifests as a failure to disengage default-mode regions in those at familial risk carrying the risk haplotype.
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http://dx.doi.org/10.1038/npp.2011.272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280657PMC
March 2012

Genetic variation in CNTNAP2 alters brain function during linguistic processing in healthy individuals.

Am J Med Genet B Neuropsychiatr Genet 2011 Dec 10;156B(8):941-8. Epub 2011 Oct 10.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

Language impairments are a characteristic feature of autism and related autism spectrum disorders (ASDs). Autism is also highly heritable and one of the most promising candidate genes implicated in its pathogenesis is contactin-associated protein-like 2 (CNTNAP2), a gene also associated with language impairment. In the current study we investigated the functional effects of variants of CNTNAP2 associated with autism and language impairment (rs7794745 and rs2710102; presumed risk alleles T and C, respectively) in healthy individuals using functional magnetic resonance imaging (fMRI) during performance of a language task (n = 66). Against a background of normal performance and lack of behavioral abnormalities, healthy individuals with the putative risk allele versus those without demonstrated significant increases in activation in the right inferior frontal gyrus (Broca's area homologue) and right lateral temporal cortex. These findings demonstrate that risk associated variation in the CNTNAP2 gene impacts on brain activation in healthy non-autistic individuals during a language processing task providing evidence of the effect of genetic variation in CNTNAP2 on a core feature of ASDs.
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http://dx.doi.org/10.1002/ajmg.b.31241DOI Listing
December 2011

The neural basis of familial risk and temperamental variation in individuals at high risk of bipolar disorder.

Biol Psychiatry 2011 Aug 24;70(4):343-9. Epub 2011 May 24.

Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Background: Bipolar disorder is a highly heritable psychiatric disorder characterized by episodic elevation or depression of mood. Bipolar disorder is associated with structural and functional brain abnormalities but it is unclear whether these are present in relatives of affected individuals and if they are associated with subclinical symptoms or traits associated with the disorder.

Methods: Functional magnetic resonance imaging scans were conducted on 93 unrelated relatives of bipolar disorder patients and 70 healthy comparison subjects performing the Hayling sentence completion paradigm. Examination of comparison subjects versus high-risk individuals was followed by assessments of associations with depression scores and measures of cyclothymic temperament.

Results: Examination of comparison subjects versus high-risk subjects revealed increased activation in the high-risk group in the left amygdala. No interaction effects were observed between the groups for scores of depression or cyclothymia and activation in any region. Significant associations were found across the groups with depression ratings and activation in the ventral striatum and with cyclothymia and activation in ventral prefrontal regions, however no interaction effects were observed between the groups.

Conclusions: Differences in activation in the left amygdala in those at familial risk may represent a heritable endophenotype of bipolar disorder. Activation in striatal and ventral prefrontal regions may, in contrast, represent a distinct biological basis of subclinical features of the illness regardless of the presence of familial risk.
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http://dx.doi.org/10.1016/j.biopsych.2011.04.007DOI Listing
August 2011

White matter integrity in individuals at high genetic risk of bipolar disorder.

Biol Psychiatry 2011 Aug 23;70(4):350-6. Epub 2011 Mar 23.

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, United Kingdom.

Background: Bipolar disorder is a familial psychiatric disorder associated with reduced white matter integrity, but it is not clear whether such abnormalities are present in young unaffected relatives and, if so, whether they have behavioral correlates. We investigated with whole brain diffusion tensor imaging whether increased genetic risk for bipolar disorder is associated with reductions in white matter integrity and whether these reductions are associated with cyclothymic temperament.

Methods: Diffusion tensor imaging data of 117 healthy unaffected relatives of patients with bipolar disorder and 79 control subjects were acquired. Cyclothymic temperament was measured with the cyclothymia scale of the Temperament Evaluation of Memphis, Pisa and San Diego auto-questionnaire. Voxel-wise between-group comparisons of fractional anisotropy (FA) and regression of cyclothymic temperament were performed with tract-based spatial statistics.

Results: Compared to the control group, unaffected relatives had reduced FA in one large widespread cluster. Cyclothymic temperament was inversely related to FA in the internal capsules bilaterally and in left temporal white matter, regions also found to be reduced in high-risk subjects.

Conclusions: These results show that widespread white matter integrity reductions are present in unaffected relatives of bipolar patients and that more localized reductions might underpin cyclothymic temperament. These findings suggest that white matter integrity is an endophenotype for bipolar disorder with important behavioral associations previously linked to the etiology of the condition.
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http://dx.doi.org/10.1016/j.biopsych.2011.01.021DOI Listing
August 2011

Functional imaging of emotional memory in bipolar disorder and schizophrenia.

Bipolar Disord 2009 Dec;11(8):840-56

Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, Scotland, UK.

Objectives: Although in current diagnostic criteria there exists a distinction between bipolar disorder and schizophrenia, many patients manifest features of both disorders, and it is unclear which aspects, if any, confer diagnostic specificity. In the present study, we investigate whether there are differences in medial temporal lobe (MTL) activation in bipolar disorder and schizophrenia. We also investigate associations between activation levels and symptom severity across the disorders.

Methods: Functional magnetic resonance imaging scans were conducted on 14 healthy controls, 14 patients with bipolar disorder, and 15 patients with schizophrenia undergoing an emotional memory paradigm.

Results: All groups demonstrated the expected pattern of behavioural responses during encoding and retrieval, and there were no significant group differences in performance. Robust MTL activation was seen in all three groups during viewing of emotional scenes, which correlated significantly with recognition memory for emotional stimuli. The bipolar group demonstrated relatively greater increases in activation for emotional versus neutral scenes in the left hippocampus than both controls and patients with schizophrenia. There was a significant positive correlation between mania scores and activation in the anterior cingulate, and a significant negative correlation between depression scores and activation in the dorsolateral prefrontal cortex.

Conclusion: These results provide evidence that there are distinct patterns of activation in the MTL during an emotional memory task in bipolar disorder and schizophrenia. They also demonstrate that different mood states are associated with different neurobiological responses to emotion across the patient groups.
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http://dx.doi.org/10.1111/j.1399-5618.2009.00768.xDOI Listing
December 2009

Genetic variation in the G72 (DAOA) gene affects temporal lobe and amygdala structure in subjects affected by bipolar disorder.

Bipolar Disord 2009 Sep;11(6):621-7

Clinica di Psichiatria, Psicologia Medica e Psicosomatica, DPMSC, University of Udine, Udine, Italy.

Background: Variation in the G72 (DAOA) gene is understood to convey susceptibility for bipolar disorder through an uncertain mechanism. Little is known about the structural brain phenotypes associated with this gene. We hypothesised that reductions in temporal lobe and amygdala gray matter would be associated with variation at two loci in the gene for which evidence of genetic linkage has been repeatedly demonstrated.

Methods: We examined the temporal lobe and amygdala gray matter associations of the risk variants M23 and M24 at the 5' end of the gene encoding G72 in 81 controls and 38 people with bipolar disorder.

Results: Genetic variation at both the M23 and M24 loci in G72 were associated with decreased gray matter density within the left temporal pole in people with bipolar disorder. M23 was also associated with reductions in right amygdala gray matter density. The genetic imaging associations were found only in patients with bipolar disorder.

Conclusions: Genetic variation at single nucleotide polymorphisms in the G72 gene previously associated with bipolar disorder is related to reductions in temporal pole and amygdala gray matter structure in people with bipolar disorder.
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http://dx.doi.org/10.1111/j.1399-5618.2009.00731.xDOI Listing
September 2009

Structural abnormalities of ventrolateral and orbitofrontal cortex in patients with familial bipolar disorder.

Bipolar Disord 2009 Mar;11(2):135-44

Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.

Objectives: Abnormalities of ventral prefrontal function have been widely reported in bipolar disorder, but reports of structural abnormalities in the same region are less consistent. We examined the presence and location of ventral prefrontal abnormalities in a large sample of individuals with bipolar disorder and their relationship to gender, psychotic symptoms, and age.

Methods: Structural magnetic resonance imaging brain scans were carried out on 66 individuals with bipolar disorder, type I, and 66 controls. Voxel-based morphometry was used to examine differences in grey and white matter density between the groups and their relationship with a lifetime occurrence of psychotic symptoms and age.

Results: Reductions in grey matter density were seen in the left and right lateral orbital gyri and the right inferior frontal gyrus, while white matter density reductions were seen in the corona radiata and the left temporal stem. In contrast, hallucinations and positive symptoms were associated with grey matter reduction in the left middle temporal gyrus. Age was more strongly associated with the right inferior frontal gyrus grey matter reductions in the bipolar group than in the controls, but not with any other finding.

Conclusion: Abnormalities of the ventral prefrontal cortex are likely to be involved in the aetiopathology of bipolar disorder, while hallucinations appear to be more closely associated with temporal lobe abnormality, extending earlier work in schizophrenia. Further prospective studies are required to comprehensively address the trajectory of these findings.
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http://dx.doi.org/10.1111/j.1399-5618.2009.00666.xDOI Listing
March 2009