Identification of comprehensive genetic factors, pathways, and shared genetic architecture of putamen volume in adolescent cohort.

Abstract

The putamen plays a key role in motor control, learning, and cognition, with abnormal putamen volumes associated with neuropsychiatric disorders. Using data from the ABCD study, we performed a genome wide association study (GWAS) of putamen volumes, followed by replication and pathway enrichment analyses. We next evaluated the shared genetic architecture of putamen volume and neuropsychiatric disorders-including depression, schizophrenia, Parkinson's, ADHD, bipolar, and OCD- using SNP associations from this and prior GWASs. We identified 142 genome-wide significant SNP associations in White participants. Most identified SNPs were in gene regulatory regions and in the neuronal growth-linked genes, DCC and DSCAM. Sixteen of the seventeen most significant associations observed in White participants were also observed in non-White participants. Seventeen known SNPs from prior GWASs of putamen volume were also replicated in our ABCD analysis, including five of the eight most significant GWAS SNPs. There was considerable genetic heterogeneity between White and non-White participants in putamen-linked SNPs with significant differences between the minor allele frequencies across the two groups (Wilcoxon rank-sum test Exact prob < 0.0001). We identified a key pathway (REACTOME_DSCAM_INTERACTIONS) associated with putamen volume that involves DSCAM gene, netrin-1 protein and/or DCC gene. In addition, 28 unique SNPs from prior GWASs of neuropsychiatric disorders were strongly associated with putamen volume at Bonferroni-corrected significance, while 41 SNPs shared by at least three disorders were associated with putamen volume at a 0.05 threshold. Our findings provide deeper insights into the shared genetic architecture and cross-population differences in genetic associations of putamen volume.