Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

N’Diaye, Amidou; Chen, Gary K.; Palmer, Cameron D.; Ge, Bing; Tayo, Bamidele O.; Mathias, Rasika A.; Ding, Jingzhong; Nalls, Michael A.; Adeyemo, Adebowale; Adoue, Véronique; Ambrosone, Christine B.; Atwood, Larry D.; Bandera, Elisa V.; Becker, Lewis C.; Berndt, Sonja I.; Bernstein, Leslie; Blot, William J.; Boerwinkle, Eric; Britton, Angela; Casey, Graham; Chanock, Stephen J.; Demerath, Ellen W.; Deming, Sandra L.; Diver, W. Ryan; Fox, Caroline S.; Harris, Tamara B.; Hernandez, Dena G.; Hu, Jennifer J.; Ingles, Sue A.; John, Esther M.; Johnson, Craig W.; Keating, Brendan J.; Kittles, Rick A.; Kolonel, Laurence N.; Kritchevsky, Stephen B.; Marchand, Loı̈c Le; Lohman, Kurt; Liu, Jiankang; Millikan, Robert C.; Murphy, Adam B.; Musani, Solomon K.; Neslund‐Dudas, Christine; North, Kari E.; Nyante, Sarah J.; Ogunniyi, Adesola; Ostrander, Elaine A.; Papanicolaou, George; Patel, Sanjay R.; Pettaway, Curtis A.; Press, Michael F.; Redline, Susan; Rodriguez-Gil, Jorge L.; Rotimi, Charles N.; Rybicki, Benjamin A.; Salako, Babatunde Lawal; Schreiner, Pamela J.; Signorello, Lisa B.; Singleton, Andrew B.; Stanford, Janet L.; Stram, Alex; Stram, Daniel O.; Strom, Sara S.; Suktitipat, Bhoom; Thun, Michael J.; Witte, John S.; Yanek, Lisa R.; Ziegler, Regina G.; Wang, Zheng; Zhu, Xiaofeng; Zmuda, Joseph M.; Zonderman, Alan B.; Evans, Michele K.; Liu, Yongmei; Becker, Diane M.; Cooper, Richard S.; Pastinen, Tomi; Henderson, Brian E.; Hirschhorn, Joel N.; Lettre, Guillaume; Haiman, Christopher A.

doi:10.1371/journal.pgen.1002298

Cited by 93 publications

(97 citation statements)

References 22 publications

(30 reference statements)

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“…HMGA2 has been associated with height determination in multiple human GWAS (Weedon et al 2007(Weedon et al , 2008Gudbjartsson et al 2008;Lettre et al 2008;Sanna et al 2008;Soranzo et al 2009;N'Diaye et al 2011;Carty et al 2012). HMGA2 is a transcription factor expressed during embryonic and fetal development (Rogalla et al 1996;Gattas et al 1999).…”

Section: Discussionmentioning

confidence: 99%

“…GWAS in humans have identified 180 loci significantly associated with height (Gudbjartsson et al 2008;Lettre et al 2008;Sanna et al 2008;Weedon et al 2008;Soranzo et al 2009;Kim et al 2010;Lango Allen et al 2010;N'Diaye et al 2011;Carty et al 2012). However, even together, these loci account for only ;10% of the adult human height variation (Lango Allen et al 2010), although the heritability of height is ;80% (Silventoinen 2003;Visscher et al 2006;Perola et al 2007).…”

Section: Discussionmentioning

confidence: 99%

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Derived variants at six genes explain nearly half of size reduction in dog breeds

et al. 2013

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Selective breeding of dogs by humans has generated extraordinary diversity in body size. A number of multibreed analyses have been undertaken to identify the genetic basis of this diversity. We analyzed four loci discovered in a previous genome-wide association study that used 60,968 SNPs to identify size-associated genomic intervals, which were too large to assign causative roles to genes. First, we performed fine-mapping to define critical intervals that included the candidate genes GHR, HMGA2, SMAD2, and STC2, identifying five highly associated markers at the four loci. We hypothesize that three of the variants are likely to be causative. We then genotyped each marker, together with previously reported size-associated variants in the IGF1 and IGF1R genes, on a panel of 500 domestic dogs from 93 breeds, and identified the ancestral allele by genotyping the same markers on 30 wild canids. We observed that the derived alleles at all markers correlated with reduced body size, and smaller dogs are more likely to carry derived alleles at multiple markers. However, breeds are not generally fixed at all markers; multiple combinations of genotypes are found within most breeds. Finally, we show that 46%-52.5% of the variance in body size of dog breeds can be explained by seven markers in proximity to exceptional candidate genes. Among breeds with standard weights <41 kg (90 lb), the genotypes accounted for 64.3% of variance in weight. This work advances our understanding of mammalian growth by describing genetic contributions to canine size determination in non-giant dog breeds.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Derived variants at six genes explain nearly half of size reduction in dog breeds

et al. 2013

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“…We created a list of 66 regions from this list of 130 SNPs by grouping SNPs located within 50 kb of each other, and then adding 10 kb to each end of each resulting start and end position (e.g., such that an individual SNP not located within 50 kb of another significant SNP would be represented in a region of 20,001 bp centered around the significantly associated SNP; Dataset S4). We also analyzed a set of candidate African stature SNPs reported by N'Diaye et al (39). The authors of this study began with a database of European GWAS height SNPs, but then identified the tag SNPs for each locus that best reflected linkage disequilibrium patterns in Africans.…”

Section: Methodsmentioning

confidence: 99%

“…S6). We also considered our 1M SNP genotype data against stature association results from two previous genomic studies of west central African rainforest huntergatherers (6,29) and with a set of candidate height SNPs for individuals of African descent (39).…”

Section: Batwa-baka Comparison Suggests Pygmy Phenotype Convergencementioning

confidence: 99%

Adaptive, convergent origins of the pygmy phenotype in African rainforest hunter-gatherers

Perry

Foll

Grenier

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The evolutionary history of the human pygmy phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (east central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses, we computed the haplotypebased integrated haplotype score (iHS) statistic and the level of population differentiation (F ST ) between the Batwa and their agricultural neighbors, the Bakiga, for each genomic SNP. Both jiHSj and F ST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (west central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated jiHSj or F ST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.human evolutionary ecology | human hunter-gatherers | population genomics | convergent evolution

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“…Furthermore, the best associated SNP in African‐derived populations was associated with LCORL gene expression levels in lymphoblastoid cell lines derived from 56 unrelated Yoruba individuals ( P = 0.0026) (N'Diaye et al . 2011). In contrast, Lango Allen et al .…”

Section: Ncapg‐lcorlmentioning

confidence: 99%

PLAG1 and NCAPG‐LCORL in livestock

Takasuga

2015

Animal Science Journal

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A recent progress on stature genetics has revealed simple genetic architecture in livestock animals in contrast to that in humans. PLAG1 and/or NCAPG‐LCORL, both of which are known as a locus for adult human height, have been detected for association with body weight/height in cattle and horses, and for selective sweep in dogs and pigs. The findings indicate a significant impact of these loci on mammalian growth or body size and usefulness of the natural variants for selective breeding. However, association with an unfavorable trait, such as late puberty or risk for a neuropathic disease, was also reported for the respective loci, indicating an importance to discriminate between causality and association. Here I review the recent findings on quantitative trait loci (QTL) for stature in livestock animals, mainly focusing on the PLAG1 and NCAPG‐LCORL loci. I also describe our recent efforts to identify the causative variation for the third major locus for carcass weight in Japanese Black cattle.

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Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

Cited by 93 publications

References 22 publications

Derived variants at six genes explain nearly half of size reduction in dog breeds

Derived variants at six genes explain nearly half of size reduction in dog breeds

Adaptive, convergent origins of the pygmy phenotype in African rainforest hunter-gatherers

PLAG1 and NCAPG‐LCORL in livestock

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