Positive Selection within the Schizophrenia-Associated GABAA Receptor β2 Gene

Wing-Sze Lo,Cunyou Zhao,Ka-Lok Tong,Gerald Stöber,Zhiwen Xu,Siu-Kin Ng,Zhiliang Yu,Shui-Ying Tsang,Hong Xue,Vishwajit L Nimgaonkar,Xiaojing Xu,Mutsuo Harano,Jianhuan Chen,Frank W Pun

doi:10.1371/journal.pone.0000462

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.

Highlights

Schizophrenia is one of the most debilitating mental disorders, afflicting peoples of all countries and cultures with about 1% lifetime risk [1]
Aguade's test is based on the neutral molecular evolution expectation that DNA sequence polymorphism
the rate of evolution in this region could be tested for departure from neutrality

Summary

Introduction

Schizophrenia is one of the most debilitating mental disorders, afflicting peoples of all countries and cultures with about 1% lifetime risk [1]. Understanding the etiology of schizophrenia paves the way to effective therapeutic treatment of the disease, but may provide important insight into the nature of human cognition. Over the past several years, advances in genomics have made possible an initial delineation of the genetic mechanisms of schizophrenia. DNA sequence polymorphisms in a number of genes are found to be associated with the disease [3]. One of the strongest associations is that discovered by our laboratory in the single nucleotide polymorphisms (SNPs) and haplotypes in introns 8 and 9 of GABRB2 [4]. GABRB2 codes for the b2 subunit of GABAA receptor, and is part of a cluster of genes on chromosome 5q34 for the GABAA receptor, the major inhibitory neurotransmitter-gated channel receptor family in the central nervous system (CNS) [5]. Our initial findings from Han Chinese have since been validated by additional samples from the Chinese [6], Portuguese [7], German [7,8,9] and Japanese [9] populations, conflicting results from Japanese [10] and German [11] populations have been reported

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Results

Discussion

Conclusion