Positive Selection within the Schizophrenia-Associated GABAA Receptor β2 Gene

Abstract

The gamma-aminobutyric acid type-A (GABAA) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABAA receptor β2 subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced β2 isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of β2, especially its long isoform. Electrophysiological analysis showed that this long β2 isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABAA receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene.

Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia

“…Notably, some other SZ candidate genes may be undergoing recent adaptive selection, such as MAOB and GARBRB2 [Lo et al, 2007], which also fit the ancestral susceptibility model. Such genes may provoke another interesting area in the genetic study of human phenotypes, by broadening one's view of diseases from a virtually static point into a dynamic one which will take the long history and thereby the evolutionary force into consideration.…”

Imprinting in the schizophrenia candidate gene GABRB2 encoding GABAA receptor β2 subunit

“…46 Because strong positive selection occurs within the schizophreniaassociated GABRB2, imprinting of this gene could make a contribution, through enhancement of evolvability, to the attainment of high derived-allele frequencies in its schizophrenia-associated SNPs: > 87% for S1, > 65% for S3, > 64% for S5 and > 69% for S29 in both US Caucasian and Chinese Han populations. 47 Thus, the observations of strong positive selection, hot-spot recombination rates 21 and the occurrence of imprinting in the GABRB2 may not be merely coincidental to the association of this segment with schizophrenia. Much more plausibly, these three kinds of genomic processes could all have a fundamental role in the etiology of schizophrenia.…”

A common haplotype of DRD3 affected by recent positive selection is associated with protection from schizophrenia

“…The other putative cases, GABRB2 and MAOB, seem to Wt the ancestral susceptibility hypothesis, which proposed that some alleles may be currently disease susceptibility variants due to a miss-adaptation between the ancestral allele and the new environment (Carrera et al 2008;Di Rienzo and Hudson 2005;Lo et al 2007). Thus, the analysis of functional candidate genes subject to recent natural selection might render new common susceptibility (or protective) alleles in future research.…”