TY - JOUR
T1 - Convergent functional genomics of genome-wide association data for bipolar disorder
T2 - Comprehensive identification of candidate genes, pathways and mechanisms
AU - Le-Niculescu, H.
AU - Patel, S. D.
AU - Bhat, M.
AU - Kuczenski, R.
AU - Faraone, S. V.
AU - Tsuang, M. T.
AU - McMahon, F. J.
AU - Schork, N. J.
AU - Nurnberger, J. I.
AU - Niculescu, A. B.
PY - 2009/3/5
Y1 - 2009/3/5
N2 - 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.
AB - 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.
KW - Bipolar
KW - Blood
KW - Brain
KW - Convergent functional genomics
KW - Gene expression
KW - Genetics
KW - Genome-wide association
UR - http://www.scopus.com/inward/record.url?scp=61449223631&partnerID=8YFLogxK
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U2 - 10.1002/ajmg.b.30887
DO - 10.1002/ajmg.b.30887
M3 - Article
C2 - 19025758
AN - SCOPUS:61449223631
SN - 1552-4841
VL - 150
SP - 155
EP - 181
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
IS - 2
ER -