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.

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

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PURPOSE. Chemokine signaling and monocytes/macrophages were implicated in the pathogenesis of AMD. We tested the association between chemokines involved in monocyte recruitment and AMD. METHODS.Immunophenotyping for white blood cell (WBC) populations including CD14þþCD16-and CD14þCD16þ monocytes, CD19þ, CD3þ, and CD16þ lymphocytes, and chemokine receptors CCR1, CCR2, CCR5, CX 3 CR1, and CXCR4 was performed on peripheral blood from treatment-naïve neovascular AMD (NV-AMD) patients and controls. The mRNA level of chemokine receptors in monocytes was measured with quantitative-PCR. Systemic levels of major chemokine ligands CCL2, CCL5, CCL3, and CXCL10 were evaluated by ELISA. Genotyping was performed for risk SNPs for AMD in the CFH, C3, and HTRA1 genes. RESULTS.The percentage of WBC subpopulations tested was similar between NV-AMD patients (n ¼ 18) and controls (n ¼ 20). CD14þCD16þ monocyte subpopulation showed a 3.5-fold increased expression of CCR1 (P ¼ 0.039; t-test) and a 2.2-fold increased expression of CCR2 (P ¼ 0.027) in patients compared with controls. Increased CCR1 and CCR2 expression was correlated with each other in patients (R 2 ¼ 0.64, P < 0.0001), but not controls (R 2 ¼ 0.02, P ¼ 0.57). Increased mRNA levels of CCR1 (1.6-fold, P ¼ 0.037) and CCR2 (1.6-fold, P ¼ 0.007) were found in monocytes from NV-AMD patients. Chemokine receptor expression was not correlated with the presence of risk SNPs, and was not associated with blood chemokine levels.CONCLUSIONS. CCR1 and CCR2 are coupregulated on the CD14þCD16þ monocyte population in NV-AMD patients. These data implicate CD14þCD16þ monocytes and chemokine signaling in AMD. Additional investigation is needed to elucidate the role of these monocytes and their potential as a biomarker or therapeutic target for AMD. (Invest Ophthalmol Vis Sci. 2012;53:5292-5300)

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