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

Jae Hoon Sul, Susan K. Service, Alden Y. Huang, Vasily Ramensky, Sun Goo Hwang, Terri M. Teshiba, Young Jun Park, Anil P.S. Ori, Zhongyang Zhang, Niamh Mullins, Loes M. Olde Loohuis, Scott C. Fears, Carmen Araya, Xinia Araya, Mitzi Spesny, Julio Bejarano, Margarita Ramirez, Gabriel Castrillón, Juliana Gomez-Makhinson, Maria C. LopezGabriel Montoya, Claudia P. Montoya, Ileana Aldana, Javier I. Escobar, Jorge Ospina-Duque, Barbara Kremeyer, Gabriel Bedoya, Andres Ruiz-Linares, Rita M. Cantor, Julio Molina, Giovanni Coppola, Roel A. Ophoff, Gabriel Macaya, Carlos Lopez-Jaramillo, Victor Reus, Carrie E. Bearden, Chiara Sabatti, Nelson B. Freimer

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17 Scopus citations


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.

Original languageEnglish (US)
Article number74
JournalTranslational psychiatry
Issue number1
StatePublished - Dec 1 2020

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry


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