Common genetic variants and gene expression associated with white matter microstructure in the human brain

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2014-08, Vol.97, p.252-261
• Main Authors: Sprooten, Emma, Knowles, Emma E., McKay, D. Reese, Göring, Harald H., Curran, Joanne E., Kent, Jack W., Carless, Melanie A., Dyer, Thomas D., Drigalenko, Eugene I., Olvera, Rene L., Fox, Peter T., Almasy, Laura, Duggirala, Ravi, Kochunov, Peter, Blangero, John, Glahn, David C.
• Format: Article
• Language: English
• Subjects: Anisotropy; Attention deficit hyperactivity disorder; Biological and medical sciences; Bipolar disorder; Brain research; Cohort Studies; Diffusion Tensor Imaging; Disease; Extended pedigrees; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression - physiology; Genealogy; Genetic Variation - physiology; Genetics; Genome-wide association; Genome-Wide Association Study; Genomes; Genotype; Health risk assessment; Humans; Mental health; Mexican Americans; Microstructure; NMR; Nuclear magnetic resonance; Polymorphism, Single Nucleotide; Studies; Vertebrates: nervous system and sense organs; White matter; White Matter - anatomy & histology; White Matter - ultrastructure
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2014.04.021

Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease. •Five genome-wide significant SNPs were detected in association with FA.•HTR7 expression is associated with FA and with intronic genome-wide significant hit.•GNA13 and CCDC91 expression may mediate effects of genome-wide significant SNPs.•Additive genetic effects on FA are largely homogeneous across white matter tracts.