A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency < 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

PNPLA3 gene in liver diseases

“…Whether numerous rare variants of large effect or common variants of very small effect make the stronger contribution to disease risk remains a topic of debate. However, in any case, the sample size required to achieve sufficient statistical power to detect new genetic variants will remain a critical issue [128,129]. In addition, rather than considering PNPLA3 alone as a biomarker for disease and outcome prediction in patients with liver disease, we advocate for the creation of large well-phenotyped cohorts with prospective follow-up.…”

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

“…Hence, we searched for any overlap between our top association signals and those previously reported for AMD [71][72][73] . Amongst our suggestive association signals we find the TIMP metallopeptidase inhibitor 3 (TIMP3)/synapsin III (SYN3) locus at 22q12.3 (Supplementary Table 2).…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…A direct involvement in disease pathology is suggested and seems plausible given the organ confined expression of MCT3 in the human retinal pigment epithelium and the importance of appropriate energy substrate shuttling between the different ocular cell types ( Figure 3). 68 …”