@article{feb2aaf2319c4bd6aa5564a77e16c9e4,
title = "Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects",
abstract = "Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson's disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 706) and the Queensland Twin Imaging Study (QTIM; N = 639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (PMA = 4. 79 × 10-8). This commonly-carried genetic variant accounted for 2. 68 % and 0. 84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster's involvement in lentiform nucleus volume differences in human populations.",
keywords = "Basal ganglia, Drug metabolism, Genome-wide association study (GWAS), MRI, Morphometry, Replication",
author = "Hibar, {Derrek P.} and Stein, {Jason L.} and Ryles, {April B.} and Omid Kohannim and Neda Jahanshad and Medland, {Sarah E.} and Hansell, {Narelle K.} and McMahon, {Katie L.} and {de Zubicaray}, {Greig I.} and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Wright, {Margaret J.} and Saykin, {Andrew J.} and Jack, {Clifford R.} and Weiner, {Michael W.} and Toga, {Arthur W.} and Thompson, {Paul M.}",
note = "Funding Information: Acknowledgments Data collection and sharing for this project was funded by the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant (U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc., F Hoffman-La Roche, Schering-Plough, Synarc, Inc., as well as non-profit partners the Alzheimer{\textquoteright}s Association and Alzheimer{\textquoteright}s Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, San Diego, CA, USA. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles, CA, USA. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. Algorithm development for this study was also funded by the NIA, NIBIB, NICHD, the National Library of Medicine, and the National Center for Research Resources (AG016570, EB01651, LM05639, RR019771, EB008432, EB008281 and EB007813, to PMT). For QTIM we thank the twins for their participation, Kori Johnson and the radiographers for MRI scanning and preprocessing the images, Marlene Grace and Ann Eldridge for twin recruitment, Daniel Park for database support, Anjali Henders for DNA processing and preparation, Scott Gordon for quality control and management of the genotypes. The QTIM study was supported by the National Institute of Child Health and Human Development (R01 HD050735), and the National Health and Medical Research Council (NHMRC 486682, 1009064), Australia. Genotyping was supported by NHMRC (389875). DPH is partially supported by NSF grant DGE-0707424. OK was supported by NIH NIA Grant F30AG041681 and the UCLA Graduate Division. JLS is partially supported by a T32 post-doctoral training grant in Neurobehavioral Genetics. NJ was additionally supported by NIH NLM Grant T15 LM07356. GM was supported by an NHMRC Fellowship 613667; GZ was supported by an ARC Future Fellowship. AJS receives support from ADNI as well as NIA R01 AG19771, P30 AG10133 and U01 AG032984.",
year = "2013",
month = jun,
doi = "10.1007/s11682-012-9199-7",
language = "English",
volume = "7",
pages = "102--115",
journal = "Brain Imaging and Behavior",
issn = "1931-7557",
publisher = "Springer New York",
number = "2",
}