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Transl Psychiatry. 2018 Mar 27;8(1):72. doi: 10.1038/s41398-018-0120-z.

Effects on gene expression and behavior of untagged short tandem repeats: the case of arginine vasopressin receptor 1a (AVPR1a) and externalizing behaviors.

Author information

1
Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, 44195, USA.
2
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA.
3
Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
4
Human Brain Collection Core, National Institutes of Mental Health, National Institutes of Health, Bethesda, MD, 20814, USA.
5
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA. davidgoldman@mail.nih.gov.
6
Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA. davidgoldman@mail.nih.gov.

Abstract

Genome-wide association studies (GWAS) of complex, heritable, behavioral phenotypes have yielded an incomplete accounting of the genetic influences. The identified loci explain only a portion of the observed heritability, and few of the loci have been shown to be functional. It is clear that current GWAS techniques overlook key components of phenotypically relevant genetic variation, either because of sample size, as is frequently asserted, or because of methodology. Here we use arginine vasopressin receptor 1a (AVPR1a) as an in-depth model of a methodologic limitation of GWAS: the functional genetic variation (in the form of short tandem repeats) of this key gene involved in affiliative behavior cannot be captured by current GWAS methodologies. Importantly, we find evidence of differential allele expression, twofold or more, in at least a third of human brain samples heterozygous for a reporter SNP in the AVPR1a transcript. We also show that this functional effect and a downstream phenotype, externalizing behavior, are predicted by AVPR1a STRs but not SNPs.

PMID:
29581423
PMCID:
PMC5913313
DOI:
10.1038/s41398-018-0120-z
[Indexed for MEDLINE]
Free PMC Article

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