Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10−3) and candidate genes from knockout mice (P = 5.2 × 10−3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000–185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts

Prevalence and correlates of eating disorders in 875 patients with bipolar disorder

Objective: Relatively little is known about the co-occurrence of bipolar and eating disorders. We therefore assessed the prevalence and clinical correlates of eating disorders in 875 patients with bipolar disorder. Method: 875 outpatients with DSM-IV bipolar I or II disorder were evaluated with structured diagnostic interviews and clinician- and self-administered questionnaires to determine bipolar and eating disorder diagnoses, other comorbid Axis I disorder diagnoses, and demographic and historical illness characteristics. Results: 125 (14.3%) patients met DSM-IV criteria for at least one comorbid lifetime Axis I eating disorder, with binge eating disorder (N = 77) being more common than bulimia nervosa (n = 42) and anorexia nervosa (N = 27). There were no significant eating disorder comorbidity differences between bipolar I and bipolar II patients. Presence of a lifetime comorbid eating disorder was associated with female gender, younger age, earlier age of onset of mood symptoms and of bipolar disorder, presentation in a mixed episode, greater number of prior mood episodes, history of rapid cycling and suicide attempts, greater mean BMI, obesity and severe obesity, and family history of depression, bipolar disorder, alcoholism, and drug abuse. When the three eating disorder groups were compared, lifetime anorexia nervosa was associated with normal weight and a lifetime anxiety disorder, lifetime bulimia nervosa was associated with overweight, and lifetime binge eating disorder was associated with obesity and severe obesity. Conclusions: Patients with bipolar disorder, especially women, not infrequently have comorbid eating disorders, and this comorbidity is associated with an earlier age of onset and more severe course of bipolar illness. (C) 2010 Elsevier B.V. All rights reserved