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. 2014 Jun 2:5:3983.
doi: 10.1038/ncomms4983.

Amerindian-specific regions under positive selection harbour new lipid variants in Latinos

Arthur Ko  1 , Rita M Cantor  2 , Daphna Weissglas-Volkov  2 , Elina Nikkola  2 , Prasad M V Linga Reddy  2 , Janet S Sinsheimer  2 , Bogdan Pasaniuc  3 , Robert Brown  4 , Marcus Alvarez  2 , Alejandra Rodriguez  2 , Rosario Rodriguez-Guillen  5 , Ivette C Bautista  6 , Olimpia Arellano-Campos  6 , Linda L Muñoz-Hernández  6 , Veikko Salomaa  7 , Jaakko Kaprio  8 , Antti Jula  7 , Matti Jauhiainen  7 , Markku Heliövaara  7 , Olli Raitakari  9 , Terho Lehtimäki  10 , Johan G Eriksson  11 , Markus Perola  12 , Kirk E Lohmueller  13 , Niina Matikainen  14 , Marja-Riitta Taskinen  14 , Maribel Rodriguez-Torres  6 , Laura Riba  5 , Teresa Tusie-Luna  5 , Carlos A Aguilar-Salinas  6 , Päivi Pajukanta  1
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Free PMC article

Amerindian-specific regions under positive selection harbour new lipid variants in Latinos

Arthur Ko et al. Nat Commun. .
Free PMC article

Abstract

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

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Figures

Figure 1
Figure 1. Minor allele frequency distributions in the Finnish and Mexican low TG controls before and after the cross-population allele screen.
(a) Displays the SNPs with a MAF≤5% in the Mexicans. These SNPs with a MAF≤5% were not pruned based on LD. (b) shows the SNPs with a MAF>5% in the Mexicans. These SNPs with a MAF>5% were pruned based on LD in the Mexican controls using an R2 cutoff of 0.5. Mantel–Haenszel (M–H) P-value is displayed, indicating that the difference between the Mexican and Finnish frequencies was significantly different after the screen, and therefore, population-stratified variants are enriched due to the CPAS.
Figure 2
Figure 2. Local ancestry difference between Mexican low TG controls and high TG cases in the genomic regions implicated by the CPAS-GWAS.
(a) Local ancestry results are shown for chromosome 8. Rs28680850 and rs79236614 were both significant after Bonferroni correction and rs4360309 displayed a suggestive signal in the GWAS. All three variants reside in regions that show Amerindian enrichment in Mexican high TG cases (>3% Amerindian ancestry difference). (b) Local ancestry difference between Mexican low TG controls and high TG cases on chromosome 11q23 where the TG risk haplotype region resides. The seven haplotype-tagging SNPs are shown as green diamonds that are clustered together in the plot. These LAMP-LD results indicate that the 11q23 region is highly enriched for Amerindian ancestry in the Mexican high TG cases.
Figure 3
Figure 3. Frequencies of the chr11 haplotypes and variants in the TG risk region.
(a) Frequencies of chr11 risk haplotypes between the Mexican TG cases and controls. The P-value of the omnibus haplotype was 1.93 × 10−24 using the haplotype case/control test in PLINK. Red bars represent the haplotype frequencies in the Mexican cases and green bars the frequencies in the Mexican controls. NS indicates nonsignificant (P>0.05). The order of the SNPs on the haplotype is rs918143 (1/C), rs964184 (1/G), rs525028 (1/G), rs139961185 (2/A), rs12366015 (1/A), rs56371319 (2/A) and rs74830 (2/T) with the TG-increasing allele given in parenthesis. (b) The minor allele frequencies of the seven haplotype SNPs in the order of Finnish TG controls, Mexican TG controls and Mexican TG cases. (c) The minor allele frequencies of the nine SNPs travelling with the two chr11 risk haplotypes in the same order of groups as in Fig. 3b above.
Figure 4
Figure 4. Analysis of natural selection in the three Mexican TG risk regions.
The absolute |iHS| were plotted across the three TG risk loci in the upper panel. A blue line indicates the top 1% chromosome-wide |iHS| threshold (>2.56). For comparison, the lower panel shows the logistic regression results of the Mexican TG case/control sample for the same SNPs (MAF>5%) in each region. LD (in R2) is plotted against the regional lead SNP. All 3,701 Mexican individuals were included in the iHS analysis. (a) The |iHS| results on chr8p21. The highest peak was observed in the LPL promoter region although no extreme |iHS| scores (>4) were observed. (b) The |iHS| results on chr8p23.3. A region harbouring a lincRNA, LOC286083 shows signs of positive selection with peaks of extreme |iHS| values. (c) The |iHS| results of chr11q23. Clusters of extreme |iHS| scores in the SIK3 region suggests that it underwent positive selection pressure in Mexicans. In the lower panel, LD is measured against rs964184 or rs139961185, respectively, before or after the 168 MB bp position, indicated by the vertical line.
Figure 5
Figure 5. Difference in postprandial TG clearance rate between rs139961185 risk allele carriers and non-carriers.
The individuals carrying the rs139961185 risk allele in SIK3 demonstrated a slower TG clearance rate (P=0.03 for AUC TG from linear regression) when compared with the non-carriers consistently (a) in Mexicans with low and high fasting TG levels at baseline and (b) in the combined study sample, suggesting that SIK3 is implicated for delayed postprandial TG clearance in Mexicans. There were 57 participants of which 3 and 9 were risk allele carriers (A/A and A/G) in the low and high TG group; and 17 and 28 were non-risk allele carriers (G/G) in the low and high TG group, respectively.
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