Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate

Benjamin Georgi, David Craig, Rachel L. Kember, Wencheng Liu, Ingrid Lindquist, Sara Nasser, Christopher Brown, Janice Egeland, Steven M. Paul, Maja Bućan

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.

Original languageEnglish
Article numbere1004229
JournalPLoS Genetics
Volume10
Issue number3
DOIs
StatePublished - Jan 1 2014

Fingerprint

Bipolar Disorder
pedigree
linkage (genetics)
genomics
Pedigree
genome
Genome
haplotypes
genotype
experimental design
Haplotypes
loci
behavior disorders
Amish
gene
Genotype
genetic disorders
risk factor
risk factors
genes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)
  • Medicine(all)

Cite this

Georgi, B., Craig, D., Kember, R. L., Liu, W., Lindquist, I., Nasser, S., ... Bućan, M. (2014). Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate. PLoS Genetics, 10(3), [e1004229]. https://doi.org/10.1371/journal.pgen.1004229

Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate. / Georgi, Benjamin; Craig, David; Kember, Rachel L.; Liu, Wencheng; Lindquist, Ingrid; Nasser, Sara; Brown, Christopher; Egeland, Janice; Paul, Steven M.; Bućan, Maja.

In: PLoS Genetics, Vol. 10, No. 3, e1004229, 01.01.2014.

Research output: Contribution to journalArticle

Georgi, B, Craig, D, Kember, RL, Liu, W, Lindquist, I, Nasser, S, Brown, C, Egeland, J, Paul, SM & Bućan, M 2014, 'Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate', PLoS Genetics, vol. 10, no. 3, e1004229. https://doi.org/10.1371/journal.pgen.1004229
Georgi B, Craig D, Kember RL, Liu W, Lindquist I, Nasser S et al. Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate. PLoS Genetics. 2014 Jan 1;10(3). e1004229. https://doi.org/10.1371/journal.pgen.1004229
Georgi, Benjamin ; Craig, David ; Kember, Rachel L. ; Liu, Wencheng ; Lindquist, Ingrid ; Nasser, Sara ; Brown, Christopher ; Egeland, Janice ; Paul, Steven M. ; Bućan, Maja. / Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate. In: PLoS Genetics. 2014 ; Vol. 10, No. 3.
@article{0c55ba14a6ad452fb10f006c63abb430,
title = "Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate",
abstract = "Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.",
author = "Benjamin Georgi and David Craig and Kember, {Rachel L.} and Wencheng Liu and Ingrid Lindquist and Sara Nasser and Christopher Brown and Janice Egeland and Paul, {Steven M.} and Maja Bućan",
year = "2014",
month = "1",
day = "1",
doi = "10.1371/journal.pgen.1004229",
language = "English",
volume = "10",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate

AU - Georgi, Benjamin

AU - Craig, David

AU - Kember, Rachel L.

AU - Liu, Wencheng

AU - Lindquist, Ingrid

AU - Nasser, Sara

AU - Brown, Christopher

AU - Egeland, Janice

AU - Paul, Steven M.

AU - Bućan, Maja

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.

AB - Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.

UR - http://www.scopus.com/inward/record.url?scp=84897466223&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897466223&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1004229

DO - 10.1371/journal.pgen.1004229

M3 - Article

C2 - 24625924

AN - SCOPUS:84897466223

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 3

M1 - e1004229

ER -