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.

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.

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

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.

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

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.

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

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.

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

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/).

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Obstetric complications and mild to moderate intellectual disability.

BACKGROUND: Mild to moderate intellectual disability affects 2.5% of the general population and is associated with an increased risk of several psychiatric disorders. Most cases are of unknown aetiology although genetic factors have an important role. AIMS: To investigate the role of obstetric and neonatal complications in the aetiology of mild to moderate intellectual disability. METHOD: Obstetric and neonatal complications recorded at the time of pregnancy and delivery were compared between participants with mild to moderate intellectual disability, age-matched siblings and unrelated controls using logistic regression. RESULTS: Admission to a special care baby unit and not being breastfed on discharge were more common in people with mild to moderate intellectual disability. Not being breastfed on discharge was also more common in those with intellectual disability than unaffected siblings. Foetal distress was more common among controls than among those with mild to moderate intellectual disability. CONCLUSIONS: Admission to a special care baby unit and not being breastfed on discharge may be related to the aetiology of intellectual disability, although the direction of this association is unclear.

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging.

OBJECTIVES: Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders. METHODS: DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis. RESULTS: Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication. CONCLUSIONS: Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.

Changes in gyrification over 4 years in bipolar disorder and their association with the brain-derived neurotrophic factor valine(66) methionine variant.

BACKGROUND: Evidence suggests that structural brain changes occur over time in bipolar disorder but few studies have examined this longitudinally. Additional work implicates brain-derived neurotrophic factor (BDNF) valine (val)(66)methionine (met) variant in these changes. The present study examined longitudinal trends in prefrontal gyrification index (GI) in bipolar disorder and the effect of BDNF genotype. METHODS: Eighteen patients with bipolar I disorder and 18 control subjects underwent magnetic resonance imaging at study entry and after 4 years. Prefrontal GI was computed as the ratio of folded inner contour to exposed outer contour. RESULTS: Ventral and dorsal GI decreased significantly with time in both cohorts; the rate did not differ for bipolar patients. Within the bipolar cohort, individuals with one or more BDNF met alleles showed greater losses in GI, an effect that correlated with gray matter loss in the left hemisphere. CONCLUSIONS: Gyrification index may be sensitive to atrophy, as well as being a neurodevelopmental measure. While the loss of prefrontal gyrification over time is not accelerated in bipolar disorder, a greater rate of loss is associated with the possession of one or more BDNF met alleles.

Genetic risk for white matter abnormalities in bipolar disorder.

White matter deficits have been demonstrated in people with bipolar disorder, schizophrenia and their unaffected relatives. These deficits are supported by evidence from post-mortem studies, including microarray investigations which have repeatedly implicated abnormal myelin-associated gene expression. Furthermore, several risk-associated genes have now been identified that encode for proteins which have effects on white matter integrity. These genes include neuregulin-1 (NRG1) polymorphisms of which have been associated with risk to bipolar disorder. NRG1 has been shown to have effects on axonal migration, myelination and oligodendrocyte function. We and others have also shown that 5' risk-associated genetic variants in NRG1 are associated with reductions in both white matter density and integrity in regions associated with prefrontal connectivity. These findings are discussed in the context of the current literature, along with possible future research directions.