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Common genetic variants influence human subcortical brain structures -…
Common genetic variants influence human subcortical brain structures
Itroduction to Results
Figure 1
Common genetic variants associated with subcortical volumes and the ICV
Table 1
Genetic variants at eight loci were significantly associated with putamen, hippocampus, caudate nucleus and ICV
Figure 2
Effect of rs945270 on KTN1 expression and putamen shape
Abstract
The highly complex structure of the human brain is strongly shaped by genetic influences1.
Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2.
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 volume5 and intracranial volume6.
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 inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
Methods
Extended Data
Extended Data Figure 1 Outline of the genome-wide association meta-analysis
Extended Data Figure 2 Ancestry inference via multi-dimensional scaling plots
Extended Data Figure 3 Genomic function is annotated near novel genome-wide significant loci
Extended Data Figure 4Quantile–quantile and forest plots from meta-analysis of discovery cohorts
Extended Data Figure 5Influence of patients with neuropsychiatric disease, age and gender on association results
Extended Data Figure 6Cross-structure analyses
Extended Data Figure 7Pathway analysis of GWAS results for each brain structure
Extended Data Figure 8Spatio-temporal maps showing expression of genes near the four significant putamen loci over time and throughout regions of the brain
Extended Data Figure 9CTCF-binding sites in the vicinity of the putamen locus marked by rs945270
Extended Data Figure 10Shape analysis in 1,541 young healthy subjects shows consistent deformations of the putamen regardless of segmentation protocol
Extended Data Figure 11The phenotypic variance explained by all common variants in this study
Supplementary Material
Supplementary Data 1
Supplementary Data 2
Acknowledgments
Footnotes
Online Content
Author Contributions
References