Next-generation gene discovery for variants of large impact on lipid traits

Rosenthal, Elisabeth; Blue, Elizabeth; Jarvik, Gail P.

doi:10.1097/mol.0000000000000156

Cited by 3 publications

(2 citation statements)

References 79 publications

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“…It is usually believed that using unrelated individuals in the GWAS of a quantitative phenotype is better than using related family members because related individuals could be “over-matched” for genotypes. However, researchers reported that for GWAS on a quantitative phenotype with related individuals, little power was lost whilst there are manifold additional advantages, including better quality control, more robust population stratification and fewer false positive (Visscher et al, 2008 ; Benyamin et al, 2009 ; Rosenthal et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Genetics of Obesity Traits: A Bivariate Genome-Wide Association Analysis

Duan

Tian

et al. 2018

Front. Genet.

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Previous genome-wide association studies on anthropometric measurements have identified more than 100 related loci, but only a small portion of heritability in obesity was explained. Here we present a bivariate twin study to look for the genetic variants associated with body mass index and waist-hip ratio, and to explore the obesity-related pathways in Northern Han Chinese. Cholesky decomposition model for 242 monozygotic and 140 dizygotic twin pairs indicated a moderate genetic correlation (r = 0.53, 95%CI: 0.42–0.64) between body mass index and waist-hip ratio. Bivariate genome-wide association analysis in 139 dizygotic twin pairs identified 26 associated SNPs with p < 10−5. Further gene-based analysis found 291 nominally associated genes (P < 0.05), including F12, HCRTR1, PHOSPHO1, DOCK2, DOCK6, DGKB, GLP1R, TRHR, MMP1, GPR55, CCK, and OR2AK2, as well as 6 enriched gene-sets with FDR < 0.05. Expression quantitative trait loci analysis identified rs2242044 as a significant cis-eQTL in both the normal adipose-subcutaneous (P = 1.7 × 10−9) and adipose-visceral (P = 4.4 × 10−15) tissue. These findings may provide an important entry point to unravel genetic pleiotropy in obesity traits.

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Section: Introductionmentioning

confidence: 99%

Genetics of Obesity Traits: A Bivariate Genome-Wide Association Analysis

Duan

Tian

et al. 2018

Front. Genet.

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“…Analyses of related individuals can have advantages over those of unrelated individuals because they allow for the efficient detection of high-impact variants with a relatively small sample size and increased power for follow-up association studies. 1 Linkage studies, which analyze phenotypic similarity among related individuals with respect to identity by descent (IBD) in a given region, may efficiently detect regions which contain multiple functional variants and they do not require functional variants to be highly concordant with genotyped markers. However, conventional linkage studies have been limited by only analyzing allele sharing among individuals with known relationships.…”

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confidence: 99%

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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Identification of selection signals by large-scale whole-genome resequencing of cashmere goats

Wan

et al. 2017

Sci Rep

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Inner Mongolia and Liaoning cashmere goats are two outstanding Chinese multipurpose breeds that adapt well to the semi-arid temperate grassland. These two breeds are characterized by their soft cashmere fibers, thus making them great models to identify genomic regions that are associated with cashmere fiber traits. Whole-genome sequencing of 70 cashmere goats produced more than 5.52 million single-nucleotide polymorphisms and 710,600 short insertions and deletions. Further analysis of these genetic variants showed some population-specific molecular markers for the two cashmere goat breeds that are otherwise phenotypically similar. By analyzing F ST and θπ outlier values, we identified 135 genomic regions that were associated with cashmere fiber traits within the cashmere goat populations. These selected genomic regions contained genes, which are potential involved in the production of cashmere fiber, such as FGF5, SGK3, IGFBP7, OXTR, and ROCK1. Gene ontology enrichment analysis of identified short insertions and deletions also showed enrichment in keratinocyte differentiation and epidermal cell differentiation. These findings demonstrate that this genomic resource will facilitate the breeding of cashmere goat and other Capra species in future.

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Next-generation gene discovery for variants of large impact on lipid traits

Cited by 3 publications

References 79 publications

Genetics of Obesity Traits: A Bivariate Genome-Wide Association Analysis

Genetics of Obesity Traits: A Bivariate Genome-Wide Association Analysis

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

Identification of selection signals by large-scale whole-genome resequencing of cashmere goats

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