Neural basis of genetic vulnerability to bipolar disorder

Abnormalities of reward processing, decision-making and emotion processing are core features of bipolar I disorder (BD). These processes are closely linked with fronto-striatal and midbrain circuitry. I sought to test whether dysfunctions of these pathways were present in BD and whether they related to genetic vulnerability to illness or resilience. I recruited twenty-five BD I patients each with their unaffected sibling, and compared them to 24 healthy age- and gender-matched controls. In chapter 1, I provide a research background and literature review. Chapter 2 describes the neuropsychological assessments which demonstrated trait-related deficits in working memory with slower processing speed representing an endophenotype. Chapter 3 describes the implicit/ explicit facial emotion processing task performed during event-related functional MRI (erfMRI). Pairwise comparisons demonstrated implicit processing was associated with increases in lingual gyrus and insula activations and explicit processing elicited reduced fusiform activations in patients compared with controls. Increased posterior cingulate activations and reductions in putamen and cerebellar activity were found in siblings compared to controls, and reductions in parietal activations were noted in siblings compared to their ill relatives. These findings suggest over-activations in regions involved in facial expression recognition and attentional shifting (lingual and insula respectively) and deactivations in a region important for the perception and recognition of faces (fusiform) represent correlates of disease expression. Additionally regional deactivations associated with category learning and attentional processing (parietal, putamen and cerebellar) and increased activations in a region involved in emotional salience (posterior cingulate) may represent adaptive responses associated with resilience. Chapter 4 describes an instrumental reward-learning task performed during erfMRI. Data were analysed at whole brain level and using a priori region of interest analyses in ventral striatum/midbrain and prefrontal cortex (PFC). Results included increased ventral striatum activation in association with the difference between observed and expected rewarding outcomes (the prediction error (PE)) in patients compared to controls. Decreased prefrontal activations were seen in the patient and sibling groups compared to controls in association with the learning of the value of the conditioned stimulus. These findings suggest that i) PE associated circuitry (striatal) overactivation, and ii) prefrontal deactivations underlie the genetic vulnerability to BD

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

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

Low birthweight and preterm birth in young people with special educational needs: a magnetic resonance imaging analysis

<p>Abstract</p> <p>Background</p> <p>Although neuroanatomical and cognitive sequelae of low birthweight and preterm birth have been investigated, little is understood as to the likely prevalence of a history of low birthweight or preterm birth, or neuroanatomical correlates of such a history, within the special educational needs population. Our aim was to address these issues in a sample of young people receiving additional learning support.</p> <p>Methods</p> <p>One hundred and thirty-seven participants aged 13–22 years, receiving additional learning support, were recruited via their schools or colleges and underwent structural magnetic resonance imaging (MRI). Obstetric records, available in 98 cases, included birthweight and gestational data in 90 and 95 cases, respectively. Both qualitative and quantitative voxel-based analyses of MRI data were conducted.</p> <p>Results</p> <p>A history of low birthweight and preterm birth was present in 13.3% and 13.7% of cases, respectively. Low birthweight and preterm birth were associated with specific qualitative anomalies, including enlargement of subarachnoid cisterns and thinning of the corpus callosum. Low birthweight was associated with reduced grey matter density (GMD) in the superior temporal gyrus (STG) bilaterally, left inferior temporal gyrus and left insula. Prematurity of birth was associated with reduced GMD in the STG bilaterally, right inferior frontal gyrus and left cerebellar hemisphere. Comparison of subjects with no history of low birthweight or preterm birth with a previously defined control sample of cognitively unimpaired adolescents (<it>n </it>= 72) demonstrated significantly greater scores for several anomalies, including thinning of the corpus callosum, loss of white matter and abnormalities of shape of the lateral ventricles.</p> <p>Conclusion</p> <p>Although a two-fold increased prevalence of a history of low birthweight and preterm birth exists within the special educational needs population, other aetiological factors must be considered for the overwhelming majority of cases. Neuroanatomical findings within this sample include qualitative anomalies of brain structure and grey matter deficits within temporal lobe structures and the cerebellum that persist into adolescence. These findings suggest a neurodevelopmental mechanism for the cognitive difficulties associated with these obstetric risk factors.</p

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

AbstractBipolar 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

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

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

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/)

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

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

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

AbstractEvidence 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

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

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 (h2 = 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