Common genetic variants influence human subcortical brain structures.

TitleCommon genetic variants influence human subcortical brain structures.
Publication TypeJournal Article
Year of Publication2015
AuthorsHibar DP, Stein JL, Renteria ME, Arias-Vasquez A, Desrivières S, Jahanshad N, Toro R, Wittfeld K, Abramovic L, Andersson M et al.
Corporate AuthorsAlzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN, IMAGEN, SYS
JournalNature
Volume520
Issue7546
Pagination224-9
Date Published2015 Apr 9
ISSN1476-4687
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Aging, Apoptosis, Brain, Caudate Nucleus, Child, Female, Gene Expression Regulation, Developmental, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Membrane Proteins, Middle Aged, Organ Size, Putamen, Sex Characteristics, Skull, Young Adult
Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

DOI10.1038/nature14101
Alternate JournalNature
PubMed ID25607358
PubMed Central IDPMC4393366
Grant List100309 / / Wellcome Trust / United Kingdom
104036 / / Wellcome Trust / United Kingdom
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
G0700704 / / Medical Research Council / United Kingdom
K99 LM011384 / LM / NLM NIH HHS / United States
K99 MH101367 / MH / NIMH NIH HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
P41 EB015922 / EB / NIBIB NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
R00 LM011384 / LM / NLM NIH HHS / United States
R01 AG040060 / AG / NIA NIH HHS / United States
R01 EB015611 / EB / NIBIB NIH HHS / United States
RF1 AG041915 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U54 EB020403 / EB / NIBIB NIH HHS / United States

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