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Genome-wide association studies in psychiatry: what have we learned?

ABSTRACT: Genome-wide association studies (GWAS) have been the focus of considerable effort in psychiatry. These efforts have markedly increased knowledge of the genetic basis of psychiatric disorders, and yielded empirical data on genetic architecture critical to addressing long-standing debates in the field. There is a now a clear path to increased knowledge of the 'parts lists' for these disorders.

SUBMITTER: Collins AL

PROVIDER: S-EPMC4188920 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association studies in psychiatry: what have we learned?

Collins Ann L AL Sullivan Patrick F PF

The British journal of psychiatry : the journal of mental science 20130101 1

Genome-wide association studies (GWAS) have been the focus of considerable effort in psychiatry. These efforts have markedly increased knowledge of the genetic basis of psychiatric disorders, and yielded empirical data on genetic architecture critical to addressing long-standing debates in the field. There is a now a clear path to increased knowledge of the 'parts lists' for these disorders. ...[more]

PMID: 23284144

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Project description:ContextThe primary goals of genome-wide association studies (GWAS) are to discover new molecular and biological pathways involved in the regulation of bone metabolism that can be leveraged for drug development. In addition, the identified genetic determinants may be used to enhance current risk factor profiles.Evidence acquisitionThere have been more than 40 published GWAS on skeletal phenotypes, predominantly focused on dual-energy x-ray absorptiometry-derived bone mineral density (BMD) of the hip and spine.Evidence synthesisSixty-six BMD loci have been replicated across all the published GWAS, confirming the highly polygenic nature of BMD variation. Only seven of the 66 previously reported genes (LRP5, SOST, ESR1, TNFRSF11B, TNFRSF11A, TNFSF11, PTH) from candidate gene association studies have been confirmed by GWAS. Among 59 novel BMD GWAS loci that have not been reported by previous candidate gene association studies, some have been shown to be involved in key biological pathways involving the skeleton, particularly Wnt signaling (AXIN1, LRP5, CTNNB1, DKK1, FOXC2, HOXC6, LRP4, MEF2C, PTHLH, RSPO3, SFRP4, TGFBR3, WLS, WNT3, WNT4, WNT5B, WNT16), bone development: ossification (CLCN7, CSF1, MEF2C, MEPE, PKDCC, PTHLH, RUNX2, SOX6, SOX9, SPP1, SP7), mesenchymal-stem-cell differentiation (FAM3C, MEF2C, RUNX2, SOX4, SOX9, SP7), osteoclast differentiation (JAG1, RUNX2), and TGF-signaling (FOXL1, SPTBN1, TGFBR3). There are still 30 BMD GWAS loci without prior molecular or biological evidence of their involvement in skeletal phenotypes. Other skeletal phenotypes that either have been or are being studied include hip geometry, bone ultrasound, quantitative computed tomography, high-resolution peripheral quantitative computed tomography, biochemical markers, and fractures such as vertebral, nonvertebral, hip, and forearm.ConclusionsAlthough several challenges lie ahead as GWAS moves into the next generation, there are prospects of new discoveries in skeletal biology. This review integrates findings from previous GWAS and provides a roadmap for future directions building on current GWAS successes.

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Genome-wide association studies in psychiatry: what have we learned?

Publications

Genome-wide association studies in psychiatry: what have we learned?

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