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Positive selection within the schizophrenia-associated GABA<inf>A</inf> receptor β<inf>2</inf> gene

Lo, WS and Xu, Z and Yu, Z and Pun, FW and Ng, SK and Chen, J and Tong, KL and Zhao, C and Xu, X and Tsang, SY and Harano, M and Stöber, G and Nimgaonkar, VL and Xue, H (2007) Positive selection within the schizophrenia-associated GABA<inf>A</inf> receptor β<inf>2</inf> gene. PLoS ONE, 2 (5).

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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 β 2 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. © 2007 Lo et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Lo, WS
Xu, Z
Yu, Z
Pun, FW
Ng, SK
Chen, J
Tong, KL
Zhao, C
Xu, X
Tsang, SY
Harano, M
Stöber, G
Nimgaonkar, VLnimga@pitt.eduNIMGA
Xue, H
ContributionContributors NameEmailPitt UsernameORCID
Date: 23 May 2007
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 2
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0000462
Schools and Programs: School of Public Health > Human Genetics
Refereed: Yes
PubMed ID: 17520021
Date Deposited: 11 Jul 2012 18:08
Last Modified: 22 Jun 2021 13:56


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