Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels

Abstract

We previously identified a low frequency (1.1%) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD=8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study (GWAS) data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD=20.98) and powerfully associated (p-value=8.1×10−50). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD>3) but only four other SNPs in this region were associated with p-values<1.0×10−4. When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p-value was 1.1×10−5. Linked and/or associated variants ranged in frequency (0.0018 to 0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r2<0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high impact genetic variants.

WITHDRAWN: Association between ADIPOQ rs2241766 polymorphism and risk of diabetic nephropathy

“…The ADIPOQ gene mapped to chromosome 3q27 is consisted of three exons and two introns [13][14][15]. This adipokine can exert antiinflammatory and anti-atherogenic effects and regulate glucose and lipid metabolism as well as insulin action [16,17].…”

Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study

“…The strongest evidence of both linkage and association in this sample was with the G45R variant in ADIPOQ with adiponectin levels (rs200573126:G>C; P = 4.53 × 10 −41 , LOD = 17.26). This finding is consistent with our previous results reporting a broad linkage peak on the distal q arm of chromosome 3 (Guo et al., ; Bowden et al., ; Hellwege et al., ). As expected, including the presence of the functional variant G45R as a covariate in the analyses greatly diminished the linkage peak (Figure S1) and decreased the magnitude of association for variants within the region.…”

“…Table S2 shows the phenotypes analyzed in this study and, where relevant, the transformations used to approximate normality. The presence of a low‐frequency variant encoding the G45R missense mutation in ADIPOQ (rs200573126:G>C) was included as a covariate for analyses involving adiponectin (ADP_G45R), as this variant is known to have a strong influence on adiponectin levels in this population (Bowden et al., ; Hellwege et al., ). Additionally, three admixture proportions were included as covariates in the association analysis.…”

A genome‐wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study

“…These phenotypes are widely used in population genetic studies and multiple significant association and linkage signals have been identified (Bowden et al, 2010;Palmer et al, 2015;Willer et al, 2013). In IRASFS, SNP association and linkage analyses were performed using these phenotypes (Hellwege et al, 2015Hellwege, Palmer, Raffield et al, 2014aHellwege, Palmer, Ziegler et al, 2014b), yet no INDEL analysis has been conducted. Therefore, we hypothesize that INDELs can be imputed based on array-based data from GWAS and with appropriate association and linkage approaches, analysis of INDELs may identify additional novel signals and provide valuable biological insights.…”