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Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.


ABSTRACT: Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P?=?0.001?~?0.007) and displayed modest increase in burdens of rare deleterious SNVs (P?=?0.047) and rare CNVs (P?=?0.002?~?0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

SUBMITTER: Sul JH 

PROVIDER: S-EPMC7039961 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Sul Jae Hoon JH   Service Susan K SK   Huang Alden Y AY   Ramensky Vasily V   Hwang Sun-Goo SG   Teshiba Terri M TM   Park YoungJun Y   Ori Anil P S APS   Zhang Zhongyang Z   Mullins Niamh N   Olde Loohuis Loes M LM   Fears Scott C SC   Araya Carmen C   Araya Xinia X   Spesny Mitzi M   Bejarano Julio J   Ramirez Margarita M   Castrillón Gabriel G   Gomez-Makhinson Juliana J   Lopez Maria C MC   Montoya Gabriel G   Montoya Claudia P CP   Aldana Ileana I   Escobar Javier I JI   Ospina-Duque Jorge J   Kremeyer Barbara B   Bedoya Gabriel G   Ruiz-Linares Andres A   Cantor Rita M RM   Molina Julio J   Coppola Giovanni G   Ophoff Roel A RA   Macaya Gabriel G   Lopez-Jaramillo Carlos C   Reus Victor V   Bearden Carrie E CE   Sabatti Chiara C   Freimer Nelson B NB  

Translational psychiatry 20200224 1


Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica  ...[more]

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