title: 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 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 (1,150 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 (0.0018-0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r (2) < 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.
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jacklyn N
authors.initials: JN
authors.lastname: Hellwege
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: W
authors.initials: W
authors.lastname: Mark Brown
authors.forename: Mark W
authors.initials: MW
authors.lastname: Brown
authors.forename: Julie T
authors.initials: JT
authors.lastname: Ziegler
authors.forename: S
authors.initials: S
authors.lastname: Sandy An
authors.forename: Sandy S
authors.initials: SS
authors.lastname: An
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Y-D
authors.initials: YD
authors.lastname: Ida Chen
authors.forename: Ida Y-D
authors.initials: IY
authors.lastname: Chen
authors.forename: Kent
authors.initials: K
authors.lastname: Taylor
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Speliotes
authors.forename: Carlos
authors.initials: C
authors.lastname: Lorenzo
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D030561:Databases, Nucleic Acid; D066264:Datasets as Topic; D005190:Family; D005260:Female; D008040:Genetic Linkage; D056426:Genetic Loci; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin