New loci and coding variants confer risk for age-related macular degeneration in East Asians

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10−22). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l−1 (P=5.82 × 10−21) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10−18), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10−11) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10−8). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

. Study power as a function of minor allele frequency and odds ratio for genetic markers A) surpassing P < 1 x 10 -4 in the discovery collection of 2,119 exudative AMD cases and 5,691 controls so that they could be brought forward for further testing in the replication stage and B) surpassing P < 5 x 10 -8 in the combined meta-analysis of 6,345 exudative AMD cases and 15,980 controls. Conditions yielding ≥80% power are shaded in light blue.

Singapore Prospective Study Program
Samples of Singapore Prospective Study Program (SP2) were from a revisit of 4 previously conducted population-based surveys carried out in Singapore, including the Thyroid and Heart Study1982-1984, 17 the National Health Survey 1992, 18 the National University of Singapore Heart Study 1993-1995, 19 and the National Health Survey 1998. 20 These studies comprise random samplings of individuals from the Singapore population aged 24 to 95 years, with disproportionate sampling stratified by ethnicity to ensure sufficient sample size in minority ethnic groups. The details of study design, subject recruitments and clinical protocols were described previously. 21,22 In brief, 5,157 subjects attended a comprehensive clinic examination at the Singapore Eye Research Institute that included systemic and ocular examination, retinal photography, and laboratory investigations. Venous blood samples were analyzed for lipid profiles at the National University Hospital Reference Laboratory for using an automated autoanalyzer (ADVIA 2400; Bayer Diagnostics, New York).
The genotyping for SP2 involved individuals of Chinese descent only. 23  on two platforms, we used the genotypes from the denser platform in our study.

Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience
The Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience (the Nagahama Study) is a community-based prospective cohort study that aims to determine the prevalence and risk factors of various diseases in a community. The details of study design and methodology have been described elsewhere. 24 In brief, residents of Nagahama City who satisfied the following criteria were recruited as participants and were examined between November 2008 and November 2010: 1) age ≥30 and ≤74 years; 2) ability to participate on one's own; 3) no significant problems communicating in Japanese; 4) no current serious diseases/symptoms or health issues; and 5) voluntarily decided to participate in this study. A total of 9,804 Japanese individuals participated in the Nagahama Study. All participants underwent fundus photography using a digital retinal camera (CR-DG10; Canon, Tokyo, Japan) in a dark room. 24 The fundus photos were graded for the individuals aged ≥50 years (N = 6,118) according to the simplified severity scale for AMD in the AREDS Study. 25 Information on smoking status and anti-lipid medication and was obtained via a self-reported questionnaire.
Smoking status was converted to Brinkman index.
Genomic DNA was extracted from peripheral blood samples by phenol-chloroform method. Of the participants, 3,712 individuals were genome-scanned using HumanHap610K Quad Arrays, HumanOmni2.5M Arrays, and/or HumanExome Arrays (Illumina Inc., San Diego, California, USA). After our standard quality control, genomic imputation was performed on 192 participants' data that had been genotyped by every platform. Finally, the data that consists of 1,756,611 SNPs of 3,248 individuals were fixed. All study procedures were approved by the ethics committee of Kyoto University Graduate School of Medicine.

Coronary Heart Disease Case-Controls Collection in Singapore
The