Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Jia, Xiaoming; Goes, Fernando S.; Locke, Adam E.; Palmer, Duncan S.; Wang, Weiqing; Cohen‐Woods, Sarah; Jackson, Anne; Jiang, Chen; Kvale, Mark N.; Mullins, Niamh; Nguyen, Hoang; Pirooznia, Mehdi; Rivera, Margarita; Ruderfer, Douglas M.; Shen, Lei; Thai, Khanh K.; Zawistowski, Matthew; Zhuang, Yongwen; Abecasis, Gonçalo R.; Akil, Huda; Bergen, Sarah E.; Burmeister, Margit; Chapman, Sinéad B.; delaBastide, Melissa; Kang, Hyun Min; Kwok, Pui‐Yan; Li, Jun Z.; Levy, Shawn; Monson, Eric; Moran, Jennifer L.; Sobell, Janet L.; Watson, Stanley J.; Willour, Virginia L.; Zöllner, Sebastian; Adolfsson, Rolf; Blackwood, Douglas; Boehnke, Michael; Breen, Gerome; Corvin, Aiden; Craddock, Nick; DiFlorio, Arianna; Hultman, Christina M.; Landén, Mikael; Lewis, Cathryn M.; McCarroll, Steven A.; McCombie, W. Richard; McGuffin, Peter; McIntosh, Andrew M.; McQuillin, Andrew; Morris, Derek W.; Myers, R; O’Donovan, Michael; Ophoff, Roel A.; Boks, Marco P.; Kahn, René S.; Ouwehand, Willem H.; Pato, Carlos N.; Pato, Michele T.; Posthuma, Daniëlle; Potash, James B.; Reif, Andreas; Sklar, Pamela; Smoller, Jordan W.; Sullivan, Patrick F.; Vincent, John B.; Walters, James; Neale, Benjamin M.; Purcell, Shaun; Risch, Neil; Schaefer, Catherine; Stahl, Eli A.; Zandi, Peter P.; Scott, Laura J.

doi:10.1038/s41380-020-01006-9

Cited by 17 publications

(23 citation statements)

References 69 publications

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“…The overlap in BD, however, remains uncertain. The BSC exome-dataset examined 3,987 BD cases ( 14 ), finding suggestive enrichment in 165 genes implicated in BD GWAS (OR = 1.9, P = 6.0 × 10 −4 ), but this finding did not replicate in the current sample (OR = 0.9, P = 0.40). Given that prior evidence of common and rare gene overlap in schizophrenia was quite modest ( 16, 17, 29 ), as sample sizes increase for both common and rare variation analyses in BD, we do expect to see a slow but steady convergence in much the same manner.…”

Section: Discussionmentioning

confidence: 75%

“…To test whether bipolar cases carry an excess of damaging coding variants, we analyzed exome-wide burden relative to controls using a logistic regression model controlling for principal components, sex, and overall coding burden (supplementary materials: exome-wide burden analyses). Drawing from previous exome sequencing studies of psychiatric disease ( 14, 16, 17 ), we restricted our attention to variants with minor allele count (MAC) ≤ 5 across the entirety of the dataset, corresponding to MAF ≤ 0.01%. We annotated variants using the Ensembl Variant Effect Predictor (VEP) ( 18 ) version 95 with the loftee plugin, and assigned variants to classes of variation.…”

Section: Resultsmentioning

confidence: 99%

“…We also examined ultra-rare PTV variant counts in the Bipolar Sequencing Consortium (BSC) ( 14 ) (supplementary materials: external validation with the BSC exome data, Table S10) exome sequence data. Non-zero count data were available for seven of the top ten genes exhibiting differences in ultra-rare PTV counts between BD cases and controls as measured by P- value in the BipEx dataset.…”

Section: Resultsmentioning

confidence: 99%

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Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

Palmer

Howrigan

Chapman

et al. 2021

Preprint

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Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.

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Section: Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

Palmer

Howrigan

Chapman

et al. 2021

Preprint

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“…Familybased studies in SCZ [7][8][9] , BD [10][11][12][13] and OCD 14 have identified multiple rare de novo and loss of function variations relevant to the biology of each syndrome. Similarly, case-control association studies in SCZ 4,5 and BD 15,16 have also identified the contribution of rare variants of large effect, advancing the current understanding of genetic architecture of these syndromes. An overview of recent findings from family based and case-control sequencing studies in SMI is presented in the supplement S1.…”

Section: Introductionmentioning

confidence: 98%

Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

Ganesh

Vemula

Bhattacharjee

et al. 2021

Preprint

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IntroductionWhole Exome Sequencing (WES) studies have provided important insights into the genetic architecture of neuropsychiatric syndromes identifying rare and novel variants in the protein-coding sequence of the genome that impact function. Variants and genes that are central to the shared biology of these clinical syndromes may be identified by WES in families with multiple affected individuals with serious mental illnesses (F-SMI).MethodsWe performed WES in 250 individuals (affected = 186, family-control = 64) from 100 families, each with ≥2 members with SMI, and 60 unrelated population-controls. Within pedigree prioritization employed criteria of 1. rarity (Minor Allele Frequency <0.1%, GnomAD South-Asian sample, 15308 exomes); 2. functional consequence (‘Loss of Function’ or ‘missense deleterious in 4/5 in silico predictions). 3. sharing by ≥3 affected members within a family. Across the sample, gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test, accounting for kinship.ResultsIn 17 families with ≥3 exome samples, we identified 79 rare predicted deleterious variants in 79 unique genes shared by ≥3 affected members and absent in 60 unrelated controls. Twenty (25.32%) genes were implicated in monogenic neurodevelopmental syndromes in Online Mendelian Inheritance in Man representing a statistically significant overrepresentation (Fisher’s Exact test OR = 2.47, p = 0.001). In gene-set wise SKAT, statistically significant association was noted for genes related to synaptic function (SKAT-p = 0.017).DiscussionIn F-SMI based WES study, we identify private, rare, protein altering variants in genes previously implicated in monogenic Mendelian neuropsychiatric syndromes; suggesting pleotropic influences in neurodevelopment between complex and monogenic syndromes.

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“…Another recent GWAS reported 64 important loci ( 6 ). Recent sequencing studies have suggested possible roles for rare mutations, although the findings are equivocal ( 7 ), as is the role of copy number variation ( 8 ). Some rare mutations may cause somatic diseases that confer a risk of bipolar disorder ( 1 , 9–11 ).…”

Section: Introductionmentioning

confidence: 99%

Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder

Nakamura

Nakajima

Kobayashi

et al. 2021

Human Molecular Genetics

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Bipolar disorder is a common mental illness occurring in approximately 1% of individuals and exhibits lifetime prevalence. Although genetic factors are known to contribute to this disorder, the genetic architecture has not yet been completely clarified. Our initial trio-based exome sequencing study of bipolar disorder showed enrichment of de novo, loss-of-function (LOF) or protein-altering mutations in a combined group with bipolar I and schizoaffective disorders, and the identified de novo mutations were enriched in calcium-related genes. These findings suggested a role for de novo mutations in bipolar disorder. The validity of these statistical associations can be demonstrated if the functional impact of the mutations on cellular function and behavior are identified. In this study, we focused on two de novo LOF mutations in calcium-related genes, EHD1 and MACF1, found in patients with bipolar disorder. We first showed that the EHD1 mutation resulted in a truncated protein with diminished effect on neurite outgrowth and inhibited endocytosis. Next, we used CRISPR/Cas9 to establish two knock-in mouse lines to model the in vivo effects of these mutations. We performed behavioral screening using IntelliCage and long-term wheel running analysis. Ehd1 mutant mice showed higher activity in the light phase. Macf1 mutant mice showed diminished attention and persistence to rewards. These behavioral alterations were similar to the phenotypes in previously proposed animal models of bipolar disorder. These findings endorse the possible role of de novo mutations as a component of the genetic architecture of bipolar disorder which was suggested by the statistical evidence.

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Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Cited by 17 publications

References 69 publications

Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder

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