REPORT Adiponectin Concentrations: A Genome-wide Association Study Sun Ha Jee, 1,2,11, * Jae Woong Sull, 3,11 Jong-Eun Lee, 4 Chol Shin, 5 Jongkeun Park, 6,7 Heejin Kimm, 1 Eun-Young Cho, 4 Eun-Soon Shin, 4 Ji Eun Yun, 1 Ji Wan Park, 8 Sang Yeun Kim, 1 Sun Ju Lee, 1 Eun Jung Jee, 1 Inkyung Baik, 9 Linda Kao, 2 Sungjoo Kim Yoon, 6,7 Yangsoo Jang, 10, * and Terri H. Beaty 2 Adiponectin is associated with obesity and insulin resistance. To date, there has been no genome-wide association study (GWAS) of adiponectin levels in Asians. Here we present a GWAS of a cohort of Korean volunteers. A total of 4,001 subjects were genotyped by using a genome-wide marker panel in a two-stage design (979 subjects initially and 3,022 in a second stage). Another 2,304 subjects were used for follow-up replication studies with selected markers. In the discovery phase, the top SNP associated with mean log adiponectin was rs3865188 in CDH13 on chromosome 16 (p ¼ 1.69 3 10 15 in the initial sample, p ¼ 6.58 3 10 39 in the second genome-wide sample, and p ¼ 2.12 3 10 32 in the replication sample). The meta-analysis p value for rs3865188 in all 6,305 individuals was 2.82 3 10 83 . The association of rs3865188 with high-molecular-weight adiponectin (p ¼ 7.36 3 10 58 ) was even stronger in the third sample. A reporter assay that evaluated the effects of a CDH13 promoter SNP in complete linkage disequilibrium with rs3865188 revealed that the major allele increased expression 2.2-fold. This study clearly shows that genetic variants in CDH13 influence adiponectin levels in Korean adults. Adiponectin in serum decreases insulin resistance and body weight by increasing lipid oxidation in muscle and other organs, such as the pancreas and liver. 1 Adiponectin is reduced among obese individuals, as well as those with diabetes mellitus or coronary heart disease. 2,3 Adiponectin circulates in several forms, principally as a low-molecular- weight hexamer (~180 kDa) and a high-molecular-weight multimer (~360 kDa). 4 Recent evidence has suggested that the high-molecular-weight adiponectin may be more strongly related to several characteristics of the metabolic syndrome complex. 5 A recent family-based study reported a shared herita- bility of adiponectin and the metabolic syndrome. 6 Identi- fication of genes controlling adiponectin levels may aid our understanding of how genes influence metabolic syn- drome and possibly obesity. 7,8 Recently, several genome- wide association studies (GWAS) for adiponectin have identified ADIPOQ (MIM 605441) and ARL15 as possibly causal. 9–11 Because these genome-wide studies were con- ducted primarily in samples from European-derived popu- lations, it remains uncertain whether these findings can be applied to other populations, especially Asian populations. Continental Asian populations have a higher percentage of body fat for a given unit of body mass index (BMI) than do Europeans. 12 However, there has been no published GWAS for adiponectin yet in an Asian population. We conducted a GWAS of adiponectin levels with the Human SNP Array 5.0 (Affymetrix) on a discovery sample of volunteers from the Korean Metabolic Syndrome Research Initiative study in Seoul. For replication purposes, we selected samples from two other areas in South Korea: Ansan and Bundang-gu, both in Gyeonggi Province; where a genome-wide marker panel was available from the former. We also tested for association with high-molec- ular-weight adiponectin by using SNPs identified from the Seoul discovery sample in a third replication sample. Subjects for the GWAS were recruited from the Korean Metabolic Syndrome Research Initiative study in Seoul, initiated in December 2005. A total of 9,128 individuals were recruited in 2006, and an additional 17,569 individ- uals were recruited in 2007. 13,14 Therefore, the total Seoul cohort included 26,697 volunteers. Volunteers from the first round had routine health examinations at the Health Promotion Center in University Hospitals between January 2006 and December 2007. From this total, 6,563 individ- uals were randomly selected for measurement of adiponec- tin levels. Of the 6,563 individuals with adiponectin, 1,004 individuals were genotyped. A total of 305 individuals were selected for having very low (33rd percentile) or very high (66th percentile) adiponectin levels and waist circumference. Another 699 individuals were randomly selected for genome-wide genotyping. A total of 1,004 1 Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul 102-752, South Korea; 2 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; 3 Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam 461-713, South Korea; 4 DNA Link, Inc., Seoul 121-850, South Korea; 5 Department of Internal Medicine, Korea University Ansan Hospital, Ansan 425-707, South Korea; 6 Research Institute of Molecular Genetics, The Catholic University of Korea, Seoul 137-701, South Korea; 7 Department of Biomedical Sciences, The Catholic University of Korea, Seoul 137-701, South Korea; 8 Department of Medical Genetics, College of Medicine, Hallym University, Chuncheon 200-702, South Korea; 9 Department of Foods and Nutrition, College of Natural Sciences, Kookmin University, Seoul 136-702, South Korea; 10 Cardiology Division and Cardiovascular Research Institute, Yonsei Univer- sity College of Medicine, Seoul 102-752, South Korea 11 These two authors equally contributed to this work *Correspondence: jsunha@yuhs.ac (S.H.J.), jangys1212@yuhs.ac (Y.J.) DOI 10.1016/j.ajhg.2010.09.004. Ó2010 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 87, 545–552, October 8, 2010 545