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Open Access Publications from the University of California

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

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

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.

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