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

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.

Neurodegenerative Disease Caregivers’ 5-HTTLPR Genotype Moderates the Effect of Patients’ Empathic Accuracy Deficits on Caregivers’ Well-Being

“…12–14,32 Other approaches (e.g., genome-wide association studies) have clear benefits, although we note that they typically do not assess tandem repeat genetic variants, such as 5-HTTLPR. 40…”

After the Honeymoon: Neural and Genetic Correlates of Romantic Love in Newlywed Marriages

“…It has been shown that in many cases single genes have very small effect sizes (for review, see Fox and Beevers, 2016). However, GWAS studies are limited in that they require very large sample sizes (Landefeld et al, 2018). Other important genetic variants may also be examined in future studies, for example, the 5-HTTLPR VNTR of the serotonin transporter gene that has been associated with differences in life history strategy and risk-acceptance in mating competition (Minkov and Bond, 2015).…”

Characterization of a Human-Specific Tandem Repeat Associated with Bipolar Disorder and Schizophrenia

“…For example, copy-number variants and expansions and contractions of micro-and mini-satellite sequences can be difficult to identify with short-read or Sanger sequencing technologies. Nevertheless, these types of mutations have been implicated in a wide range of neurological diseases, including Huntington disease, spinocerebellar ataxia, fragile X syndrome, depression, and aggression and impulsivity behaviors, [33][34][35][36][37][38][39][40] and likely contribute to undetected variation and missing heritability for additional human traits. 41,42 To search for unrecognized copy-number variants at the CACNA1C locus, we examined regions of the genome where no mutations were identified by large-scale sequencing projects such as the 1000 Genomes Project, 43 yet DNA sequencing reads consistently differed from the reference human assembly.…”