Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects.
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 (P MA  = 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.
Imaging Genetics Center at the Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Neuroscience Research Building 225E 635 Charles Young Drive, Los Angeles, CA, 90095-1769, USA.
Derrek P
DP
Hibar
Jason L
JL
Stein
April B
AB
Ryles
Omid
O
Kohannim
Neda
N
Jahanshad
Sarah E
SE
Medland
Narelle K
NK
Hansell
Katie L
KL
McMahon
Greig I
GI
de Zubicaray
Grant W
GW
Montgomery
Nicholas G
NG
Martin
Margaret J
MJ
Wright
Andrew J
AJ
Saykin
Clifford R
CR
Jack
Michael W
MW
Weiner
Arthur W
AW
Toga
Paul M
PM
Thompson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000473:pathology*; D003342:Corpus Striatum / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult