Population-specific coding variant underlies genome-wide association with adiponectin level.
Adiponectin is a protein hormone that can affect major metabolic processes including glucose regulation and fat metabolism. Our previous genome-wide association (GWA) study of circulating plasma adiponectin levels in Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) detected a 100 kb two-SNP haplotype at KNG1-ADIPOQ associated with reduced adiponectin (frequency = 0.050, P = 1.8 × 10(-25)). Subsequent genotyping of CLHNS young adult offspring detected an uncommon variant [minor allele frequency (MAF) = 0.025] located ~800 kb from ADIPOQ that showed strong association with lower adiponectin levels (P = 2.7 × 10(-15), n = 1695) and tagged a subset of KNG1-ADIPOQ haplotype carriers with even lower adiponectin levels. Sequencing of the ADIPOQ-coding region detected variant R221S (MAF = 0.015, P = 2.9 × 10(-69)), which explained 17.1% of the variance in adiponectin levels and largely accounted for the initial GWA signal in Filipinos. R221S was not present in 12 514 Europeans with previously sequenced exons. To explore the mechanism of this substitution, we re-measured adiponectin level in 20 R221S offspring carriers and 20 non-carriers using two alternative antibodies and determined that the presence of R221S resulted in artificially low quantification of adiponectin level using the original immunoassay. These data provide an example of an uncommon variant responsible for a GWA signal and demonstrate that genetic associations with phenotypes measured by antibody-based quantification methods can be affected by uncommon coding SNPs residing in the antibody target region.
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Damien C
DC
Croteau-Chonka
Ying
Y
Wu
Yun
Y
Li
Marie P
MP
Fogarty
Leslie A
LA
Lange
Christopher W
CW
Kuzawa
Thomas W
TW
McDade
Judith B
JB
Borja
Jingchun
J
Luo
Omar
O
AbdelBaky
Terry P
TP
Combs
Linda S
LS
Adair
Ethan M
EM
Lange
Karen L
KL
Mohlke
D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male
D052242:Adiponectin