Obesity shows an inconsistent association with cataract. Causality has not been established. Polymorphisms at the fat mass- and obesity-associated (FTO) locus are associated with obesity and offer an opportunity to examine the obesity-cataract association using a mendelian randomization approach. The authors conducted a population-based study among Singaporean Malay adults (2004-2006) in which nuclear, cortical, and posterior subcapsular (PSC) cataracts were assessed and defined by slit-lamp examination using Lens Opacity Classification System III. Obesity was defined as body mass index (weight (kg)/height (m)(2)) > or =30. The study included 3,000 subjects, of whom 1,339 (44.6%) had cataract (848 (28.3%) nuclear, 939 (31.3%) cortical, and 285 (9.5%) PSC). After multivariable adjustment for age, gender, diabetes, hypertension, smoking, and education, obesity was significantly associated with cortical (odds ratio (OR) = 1.31, 95% confidence interval (CI): 1.01, 1.71) and PSC (OR = 1.60, 95% CI: 1.10, 2.32) cataracts but not nuclear cataract. FTO single nucleotide polymorphisms known to be associated with obesity in this study population were not associated with cortical or PSC cataract but were associated with nuclear cataract (OR = 1.33, 95% CI: 1.11, 1.58), even in multivariate analyses controlling additionally for body mass index, diabetes, hypertension, and smoking (OR = 1.30, 95% CI: 1.08, 1.55). These results do not support a causal association between obesity and cortical or PSC cataract. The FTO gene may be involved in the pathogenesis of nuclear cataract.