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

Ko, Arthur; Cantor, Rita M.; Weissglas‐Volkov, Daphna; Nikkola, Elina; Reddy, Prasad M. V. Linga; Sinsheimer, Janet S.; Paşaniuc, Bogdan; Brown, Robert; Alvarez, Marcus; Rodríguez, Alejandra; Rodríguez‐Guillén, Rosario; Bautista, Ivette Cruz; Arellano-Campos, Olimpia; Muñóz-Hernández, Linda Liliana; Salomaa, Veikko; Kaprio, Jaakko; Jula, Antti; Jauhiainen, Matti; Heliövaara, Markku; Raitakari, Olli T.; Lehtimäki, Terho; Eriksson, Johan G.; Perola, Markus; Lohmueller, Kirk E.; Matikainen, Niina; Taskinen, Marja‐Riitta; Rodrı́guez-Torres, Maribel; Riba, Laura; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Pajukanta, Päivi

doi:10.1038/ncomms4983

Cited by 87 publications

(86 citation statements)

References 74 publications

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“…Within the 11q23.3 region, we focused on chromosome 11:116,600,001-117,100,000 where previous GWAS fi ndings were localized ( 16,17,23,24 ). In order to identify the independent effects of candidate loci on TG, we used the following methods.…”

Section: Dissecting the 11q233 Regionmentioning

confidence: 99%

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Bayasgalan

Lee

Kho

et al. 2016

Journal of Lipid Research

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Section: Dissecting the 11q233 Regionmentioning

confidence: 99%

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Bayasgalan

Lee

Kho

et al. 2016

Journal of Lipid Research

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“…We, thus, analyzed 11 SNPs, including 6 established TG-associated SNPs (collectively called “GWAS SNPs”, including rs964184, rs3135506, rs651821, rs662799, rs12225230, and rs139961185). 10–19 As shown in Table 1, there was no tag SNP for rs147210663 nor rs11357208. The SNP rs2072560 had 3 tag SNPs (one of them, rs651821, was also identified in several published GWAS reports).…”

Section: Resultsmentioning

confidence: 99%

“…10, 12–15, 19, 25, 37, 38 Previous studies in Amerindian-derived populations have identified strong associations between TG and variants in this chromosomal region, particularly rs964184. 14, 19, 39 SIK3 has been suggested as a functional candidate based on evidence for recent natural selection centered on rs139961185. 19 In our study, however, rs139961185 was not associated with TG after conditioning on rs964184 (Table S3 in the Data Supplement).…”

Section: Discussionmentioning

confidence: 98%

Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an APOC3 Founder Mutation

Hsueh

Nair

Kobes

et al. 2017

Circ Cardiovasc Genet

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Background Identity-by-descent (IBD) mapping using empirical estimates of IBD allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. Methods and Results Through IBD mapping, using ~400,000 SNPs, of serum lipid profiles we identified a major linkage signal for triglycerides (TG) in 1,007 Pima Indians (LOD=9.23, p=3.5×10−11 on chromosome 11q). In subsequent fine-mapping and replication association studies in ~7,500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in APOC3 (rs147210663) and 3 established functional SNPs in APOA5. The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower TG (β=−0.92±0.059 SD unit, p=9.6×10−55 in 4,668 Pimas and 2,793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations, but has a frequency of 2.5% in Pimas. We further demonstrated that 3 APOA5 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for TG identified by genome-wide association studies (GWAS). Collectively these 4 SNPs account for 6.9% of variation in TG in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null. Conclusions APOC3/APOA5 constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants.

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“…Preliminary research reported that lipid disorders (cholesterol and triglycerides) are more frequent in Amerindian-derived populations than in Europeans, justifying our results. 24 However, further studies are required to verify the association across different ethnicities.…”

Section: Discussionmentioning

confidence: 99%

PPARG-LYPLAL1 Multi-Allelic Combination Associated with Obesity and Overweight in Mexican Adolescent Females

et al. 2016

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Objective: We studied multi-loci variants to identify the contribution of six candidate genes (ADIPOQ, CDH13, LYPLAL1, MC4R, PPARG and PGC1A) in the development of obesity and overweight. Design:We genotyped 404 chromosomes with eleven SNPs in Mexican female adolescents, who were subdivided into two groups (obesity-overweight and normal-weight) using the World Health Organization parameters. Genomic (800 chromosomes) and ancestral (208 chromosomes) controls were included to reduce the population bias. Anthropometric measurements, biochemical parameters, and caloric intake were obtained only in the groups of Mexican female adolescents. Results:A positive genotype-phenotype association was found that involves the multi-allelic combination of three risk alleles (one in PPARG and two in LYPLAL1) with obesity and overweight (OR=3.1, P=.010). This combination also exhibited a significant association with waist circumference (P=.030) and triglycerides levels (P=.030). These associations were supported by a logistic regression analysis adjusted for several confounding variables. Conclusions:Our data suggest the joint participation of PPARG-LYPLAL1 genes in metabolic disorders development. Hence, these genes could act as potential biomarkers in obesity and overweight. Our findings underscore the complexity of metabolic disorders and provide evidence about the importance of multi-loci analysis to study complex diseases. Ethn Dis.

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

Cited by 87 publications

References 74 publications

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an APOC3 Founder Mutation

PPARG-LYPLAL1 Multi-Allelic Combination Associated with Obesity and Overweight in Mexican Adolescent Females

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