Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.

Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues

Genome-wide association study identifies three novel loci for type 2 diabetes

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10−8), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.This work was partly supported by a grant from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology-Japan. The work of the Shanghai Jiao Tong University was supported from grants from the National 973 Program (2011CB504001), 863 Program (2012AA02A509) and National Science Foundation of China (81322010). R.C.W.M. and J.C.N.C. acknowledge support from the Hong Kong Foundation for Research and Development in Diabetes, established under the auspices of the Chinese University of Hong Kong, the Innovation and Technology Fund (ITS/088/08 and ITS/487/09FP)), and the Research Grants Council Theme-based Research Scheme (T12–402/13-N). The work by the Shanghai Diabetes Genetic Study (SDGS) was supported in part by the US National Institutes of Health grants R37CA070867, R01CA124558, R01CA64277 and UL1 RR024975, the Department of Defense Idea Award BC050791, Vanderbilt Ingram professorship funds and the Allen Foundation Fund. We thank the dedicated investigators and staff members from research teams at Vanderbilt University, Shanghai Cancer Institute and the Shanghai Institute of Preventive Medicine, and especially the study participants for their contributions in the studies. This study was provided with data from the Korean Genome Analysis Project (4845-301), the Korean Genome and Epidemiology Study (4851-302) and Korea Biobank Project (4851-307, KBP-2013-11 and KBP-2014-68) that were supported by the Korea Center for Disease Control and Prevention, Republic of Korea. This research was supported by an intramural grant from the Korea National Institute of Health (2014-NI73001-00), Republic of Korea. This study was supported by a grant of the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI14C0060). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). The Danish studies, Inter99 and Health2006, were partly funded by the Lundbeck Foundation and produced by The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp, www.lucamp.org). The Asian Indian Diabetic Heart Study/Sikh Diabetes Study (AIDHS/SDS) was supported by the National Institute of Health grants KO1TW006087 funded by the Fogarty International Center, R01DK082766 funded by National Institute of Diabetes and Digestive and Kidney Diseases, and a seed grant from University of Oklahoma Health Sciences Center, Oklahoma City, USA. We thank the research participants for their contribution and support for making this study possible. A.H.C. was supported by a fellowship from CONACyT-Mexico. J.M.M. was supported by Sara Borrell Fellowship from the Instituto Carlos III, grant SEV-2011-00067 of Severo Ochoa Program and EMBO short-term fellowship, EFSD/Lilly research fellowship and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). SIGMA study was supported by the Slim Foundation. Y.S.C. acknowledges support from the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2012R1A2A1A03006155). Field-work, genotyping and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, EU Framework 6-funded Bloodomics Integrated Project, Pfizer, Novartis and Merck. J.D. acknowledges that this work was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834) and European Commission Framework Programme 7 (HEALTH-F2-2012-279233)