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Transl Psychiatry. 2020 Feb 24;10(1):74. doi: 10.1038/s41398-020-0758-1.

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

Author information

1
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
2
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA.
3
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
4
Federal State Institution "National Medical Research Center for Preventive Medicine" of the Ministry of Healthcare of the Russian Federation. Petroverigskiy lane 10, Moscow, 101990, Russia.
5
Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
6
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
7
King's College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
8
Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
9
Cell and Molecular Biology Research Center, Universidad de Costa Rica, San Pedro de Montes de Oca, San José, 11501, Costa Rica.
10
Division of Pediatric Pulmonology, Hospital Nacional de Nin ̃os, San Jose, Costa Rica.
11
Instituto de Alta Tecnologia Medica, Medellín, Antioquia, Colombia.
12
Department of Neuroradiology, Klinikum rechts der Isar, TUM, Munich, Germany.
13
Grupo de Investigación en Psiquiatría (Research Group in Psychiatry; GIPSI), Departamento de Psiquiatría Facultad de Medicina, Universidad de Antioquia, Medellín, 050011, Colombia.
14
Department of Psychiatry and Family Medicine, Rutgers-Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 08901, USA.
15
Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK.
16
Laboratory of Molecular Genetics, Institute of Biology, University of Antioquia, Medellín, 050010, Colombia.
17
Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, 200438, China.
18
Aix Marseille Univ, CNRS, EFS, ADES, Marseille, France.
19
Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
20
BioCiencias Lab, 01010, Guatemala, Guatemala.
21
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
22
Mood Disorders Program, Hospital San Vicente Fundacion, Medellín, 050011, Colombia.
23
Department of Psychiatry and UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, 94143, USA.
24
Department of Psychology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
25
Department of Health Research and Policy, Division of Biostatistics, Stanford University, Stanford, CA, 94305, USA.
26
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA. nfreimer@mednet.ucla.edu.
27
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University California Los Angeles, Los Angeles, CA, USA. nfreimer@mednet.ucla.edu.
28
Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA. nfreimer@mednet.ucla.edu.

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.

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