Aims/hypothesisHuman complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.MethodsThe study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans.ResultsExome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10).Conclusions/interpretationWe applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Variants in the chromodomain helicase DNA‐binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate‐to‐severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non‐ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex‐dependent penetrance of CHD8 PTVs in humans.

The objective of this paper was to objectively evaluate the effectiveness of home-based exercise interventions for improving health-related quality of life in patients with ankylosing spondylitis (AS). Databases including PubMed, Web of Science, EMBASE, Ovid-Medline, and The Cochrane Library were electronically searched published from inception through October 2014 involving home-based exercise intervention in AS patients. Studies that measured the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), depression and pain as outcomes were included. Studies involving patients with multiple diseases or received combinations of other interventions were excluded. Two independent investigators screened the identified articles, extracted the data, and assessed the methodological quality of the included studies. Qualitative descriptions were conducted, and quantitative analysis was performed with RevMan software (version 5.2). A total of six studies comprising 1098 participants were included in the study. Meta-analyses showed that home-based exercise interventions significantly reduced the BASFI scores (MD = -0.39, 95 % CI -0.57, -0.20, p = 0.001), BASDAI scores (MD = -0.50, 95 % CI -0.99, -0.02, p = 0.04), depression scores (MD = -2.31, 95 % CI -3.33, -1.30, p = 0.001), and for pain scores because of different evaluation methods among these studies; therefore, a subgroup analysis should be conducted for comparison. The results show that home-based exercise interventions can effectively improve the health-related quality of life in patients with AS. The benefit and clinical performance of home-based exercise care requires further investigation by a series of multicenter, large-sample size randomized controlled trails.

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