Recent Positive Selection Drives the Expansion of a Schizophrenia Risk Nonsynonymous Variant at SLC39A8 in Europeans

Abstract

Natural selection has played important roles in optimizing complex human adaptations. However, schizophrenia poses an evolutionary paradox during human evolution, as the illness has strongly negative effects on fitness, but persists with a prevalence of ~0.5% across global populations. Recent studies have identified numerous risk variations in diverse populations, which might be able to explain the stable and high rate of schizophrenia morbidity in different cultures and regions, but the questions about why the risk alleles derived and maintained in human gene pool still remain unsolved. Here, we studied the evolutionary pattern of a schizophrenia risk variant rs13107325 (P < 5.0 × 10(-8) in Europeans) in the SLC39A8 gene. We found the SNP is monomorphic in Asians and Africans with risk (derived) T-allele totally absent, and further evolutionary analyses showed the T-allele has experienced recent positive selection in Europeans. Subsequent exploratory analyses implicated that the colder environment in Europe was the likely selective pressures, ie, when modern humans migrated "out of Africa" and moved to Europe mainland (a colder and cooler continent than Africa), new alleles derived due to positive selection and protected humans from risk of hypertension and also helped them adapt to the cold environment. The hypothesis was supported by our pleiotropic analyses with hypertension and energy intake as well as obesity in Europeans. Our data thus provides an intriguing example to illustrate a possible mechanism for maintaining schizophrenia risk alleles in the human gene pool, and further supported that schizophrenia is likely a product caused by pleiotropic effect during human evolution.

Keywords: Europe; SLC39A8; nonsynonymous SNP; pleiotropic effects; positive selection; schizophrenia.

Fig. 1.

(A) Plot of chromosome region showing a genomic area of LD with rs13107325 in European populations. (B) Global distributions of rs13107325 in 53 world populations.

Fig. 2.

Localization of the amino acid (p391) encoded by rs13107325 at the protein level. (A) The amino acid encoded by rs1310735 is completely conserved in vertebrates, with all of the species showing alanine (corresponding to ancestral C-allele). (B) The amino acid corresponds to rs13107325 is located in the sixth transmembrane domain of SLC39A8. (C) 3D protein structure modeling reveals the spatial position of the amino acid encoded by rs13107325.

Fig. 3.

The iHS and association results with schizophrenia in PGC2 study for the SNPs in the genomic region of chr4:102900000–103300000 in European populations.

Fig. 4.

Extended haplotype homozygosity (EHH, A) and relative EHH (REHH, B) plots of core SNP rs13107325 in European populations from 1000-Human-Genome; EHH and REHH plots of core SNP rs13107325 in populations from European mainland (C and D) and Middle East (E and F) from HGDP-CEPH databases. The EHH and REHH values are plotted against the physical distance extending both upstream and downstream of the selected core region.

Fig. 5.

Haplotype networks consisting of 54 SNPs spanning a 4-kb region encompassing rs13107325. Each node represents a haplotype, and the size is proportional to its frequency.

Fig. 6.

The association results of SNPs in the genomic region of chr4:102900000–103300000 with human traits. (A) association of SBP in the discovery sample of Ehret et al., (B) association of SBP in the discovery sample of Ehret et al., (C) association of BMI in the discovery sample of Speliotes et al.

Fig. 7.

Hypothesis about positive selection and schizophrenia in European populations.