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.

INTRODUCTION The surgical management of symptomatic giant hiatus hernia (GHH) aims to improve quality of life (QoL) and reduce the risk of life threatening complications. Previous reports are predominantly those with small sample sizes and short follow-up periods. The present study sought to assess a large cohort of patients for recurrence and QoL over a longer time period. METHODS This was a follow-up study of a prospectively collected database of 455 consecutive patients. Primary repair of GHH was evaluated by endoscopy/barium meal for recurrence and a standardised symptom questionnaire for QoL. Recurrence was assessed for size, elapsed time, oesophagitis and symptoms. RESULTS Objective and subjective review was achieved in 91.9% and 68.6% of patients. The median age was 69 years (range: 15-93 years) and 64% were female. Laparoscopic repair was completed in 95% (mesh in 6% and Collis gastroplasty in 7%). The 30-day mortality rate was 0.9%. The proportion of patients alive at five and ten years were 90% and 75% respectively. Postoperative QoL scores improved from a mean of 95 to 111 (p<0.01) and were stable over time (112 at 10 years).The overall recurrence rate was 35.6% (149/418) at 42 months; this was 11.5% (48/418) for hernias >2cm and 24.2% (101/418) for <2cm. The rate of new recurrence at 0-1 years was 13.7% (>2cm = 3.4%, <2cm = 10.3%), at 1-5 years it was 30.8% (>2cm = 9.5%, <2cm = 21.3%), at 5-10 years it was 40.1% (>2cm = 13.8%, <2cm = 26.3%) and at over 10 years it was 50.0% (>2cm = 25.0%, <2cm = 25.0%). Recurrence was associated with oesophagitis but not decreased QoL. Revision surgery was required in 4.8% of cases (14.8% with recurrence). There were no interval major GHH complications. CONCLUSIONS Surgery has provided sustained QoL improvements irrespective of recurrence. Recurrence occurred progressively over ten years and may predispose to oesophagitis.

One in 10 Malay, Indian, and Chinese Singaporeans 40 years of age or older underwent cataract surgery in at least 1 eye over 6 years. In Asian populations, diabetes and myopia, 2 well-known factors associated with cataract prevalence, are significant and potentially modifiable factors associated with the need for cataract surgery.