Abstract
Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
Original language | English |
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Pages (from-to) | 5239-5250 |
Number of pages | 12 |
Journal | Molecular Psychiatry |
Volume | 26 |
Issue number | 9 |
Early online date | 22 Jan 2021 |
DOIs | |
Publication status | Published - Sept 2021 |
Bibliographical note
Funding Information:Acknowledgements Funding for this study is from: International Bipolar Sequencing Consortium (NIMH R01 MH 110437) (P.Z. M.B., J.P., N.F., P.S.); Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH UO1 MH105653) (M.B, R.M. M.); Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH R01 MH 094145) (M.B.); Multi-ethnic GWAS of Bipolar I Disorder (NIH R01 MH 085543) (C.S.); Genetic Epidemiology Research in Adult Health and Aging (GERA RC2 AG036607) (C.S., N.R.) from the Kaiser Permanente Research Program on Genes, Environment, and Health; Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH R01 MH 087979 and MH 087992) (J.P., W.R.M); 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH095034) (E.A.S.); 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106531) (E.A.S.); 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH077139) (P.F.S.); 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106527) (S.A.M.); The Dalio Foundation (B.N.).
Funding Information:
Conflict of interest XJ had no conflicts during the time he contributed to this study, and declares he is now an employee at Genentech. AEL and EAS had no conflicts during the time they contributed to this study, and declare they are now employees at Regeneron. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck pharmaceutical. CL is a member of the Myriad Neuroscience R&D SAB. BN is a Deep Genomics-Member, Scientific Advisory Board; Camp4 Therapeutics Corporation-Consultant, Scientific Advisory Board; Takeda Pharmaceutical-Consultant; Biogen-Consultant, Genomics Analytics Advisory Panel. MO has a research grant from Takeda Pharmaceuticals. JS is an unpaid member of the Bipolar/ Depression Research Community Advisory Panel of 23andMe.
Publisher Copyright:
© 2021, The Author(s).
Funding
Acknowledgements Funding for this study is from: International Bipolar Sequencing Consortium (NIMH R01 MH 110437) (P.Z. M.B., J.P., N.F., P.S.); Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH UO1 MH105653) (M.B, R.M. M.); Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH R01 MH 094145) (M.B.); Multi-ethnic GWAS of Bipolar I Disorder (NIH R01 MH 085543) (C.S.); Genetic Epidemiology Research in Adult Health and Aging (GERA RC2 AG036607) (C.S., N.R.) from the Kaiser Permanente Research Program on Genes, Environment, and Health; Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH R01 MH 087979 and MH 087992) (J.P., W.R.M); 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH095034) (E.A.S.); 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106531) (E.A.S.); 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden (R01MH077139) (P.F.S.); 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder (R01MH106527) (S.A.M.); The Dalio Foundation (B.N.). Conflict of interest XJ had no conflicts during the time he contributed to this study, and declares he is now an employee at Genentech. AEL and EAS had no conflicts during the time they contributed to this study, and declare they are now employees at Regeneron. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck pharmaceutical. CL is a member of the Myriad Neuroscience R&D SAB. BN is a Deep Genomics-Member, Scientific Advisory Board; Camp4 Therapeutics Corporation-Consultant, Scientific Advisory Board; Takeda Pharmaceutical-Consultant; Biogen-Consultant, Genomics Analytics Advisory Panel. MO has a research grant from Takeda Pharmaceuticals. JS is an unpaid member of the Bipolar/ Depression Research Community Advisory Panel of 23andMe.
Funders | Funder number |
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International Bipolar Sequencing Consortium | |
Rare Bipolar Loci Identification Through Synaptome Sequencing | R01 MH 087979, MH 087992 |
National Institutes of Health | |
National Institute of Mental Health | R01MH077139, R01 MH 110437, R01MH087992, R01MH106527, R01MH087979, R01 MH 085543, R01MH095034, R01MH106531, U01MH105653, R01 MH 094145 |
National Institute on Aging | GERA RC2 AG036607 |
Robert Wood Johnson Foundation | |
Wayne and Gladys Valley Foundation | |
Takeda Pharmaceuticals North America | |
Dalio Foundation | |
Kaiser Permanente Washington Health Research Institute |