Convergent functional genomics of genome-wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms

H. Le-Niculescu, S. D. Patel, M. Bhat, R. Kuczenski, S. V. Faraone, M. T. Tsuang, F. J. McMahon, N. J. Schork, J. I. Nurnberger, A. B. Niculescu

Research output: Contribution to journalArticle

Abstract

Given the mounting convergent evidence implicating many more genes in complex disorders such as bipolar disorder than the small number identified unambiguously by the first-generation Genome-Wide Association studies (GWAS) to date, there is a strong need for improvements in ethodology. One strategy is to include in the next generation GWAS larger numbers of subjects, and/or to pool independent studies into meta-analyses. We propose and provide proof of principle for the use of a complementary approach, convergent functional genomics (CFG), as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach. With the CFG approach, the integration of genetics with genomics, of human and animal model data, and of multiple independent lines of evidence converging on the same genes offers a way of extracting signal from noise and prioritizing candidates. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder, yielding a series of novel (such as Klf12, Aldh1a1, A2bp1, Ak3l1, Rorb, Rora) and previously known (such as Bdnf, Arntl, Gsk3b, Disc1, Nrg1, Htr2a) candidate genes, blood bio-markers, as well as a comprehensive identification of pathways and mechanisms. These become prime targets for hypothesis driven follow-up studies, new drug development and personalized medicine approaches.

Original languageEnglish (US)
Pages (from-to)155-181
Number of pages27
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume150
Issue number2
DOIs
StatePublished - Mar 5 2009
Externally publishedYes

Fingerprint

Genetic Association Studies
Genomics
Bipolar Disorder
Genome-Wide Association Study
Genome
Genes
Precision Medicine
Meta-Analysis
Animal Models
Pharmaceutical Preparations

Keywords

  • Bipolar
  • Blood
  • Brain
  • Convergent functional genomics
  • Gene expression
  • Genetics
  • Genome-wide association

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Convergent functional genomics of genome-wide association data for bipolar disorder : Comprehensive identification of candidate genes, pathways and mechanisms. / Le-Niculescu, H.; Patel, S. D.; Bhat, M.; Kuczenski, R.; Faraone, S. V.; Tsuang, M. T.; McMahon, F. J.; Schork, N. J.; Nurnberger, J. I.; Niculescu, A. B.

In: American Journal of Medical Genetics - Neuropsychiatric Genetics, Vol. 150, No. 2, 05.03.2009, p. 155-181.

Research output: Contribution to journalArticle

Le-Niculescu, H, Patel, SD, Bhat, M, Kuczenski, R, Faraone, SV, Tsuang, MT, McMahon, FJ, Schork, NJ, Nurnberger, JI & Niculescu, AB 2009, 'Convergent functional genomics of genome-wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms', American Journal of Medical Genetics - Neuropsychiatric Genetics, vol. 150, no. 2, pp. 155-181. https://doi.org/10.1002/ajmg.b.30887
Le-Niculescu, H. ; Patel, S. D. ; Bhat, M. ; Kuczenski, R. ; Faraone, S. V. ; Tsuang, M. T. ; McMahon, F. J. ; Schork, N. J. ; Nurnberger, J. I. ; Niculescu, A. B. / Convergent functional genomics of genome-wide association data for bipolar disorder : Comprehensive identification of candidate genes, pathways and mechanisms. In: American Journal of Medical Genetics - Neuropsychiatric Genetics. 2009 ; Vol. 150, No. 2. pp. 155-181.
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