We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10 −8 , relative risk in homozygotes = 1.84, 95% CI 1.34-2.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10 −8 , relative risk in homozygotes = 2.17, 95% CI 1.32-3.56).NSCL/P is one of the most common human birth defects. In European populations, NSCL/P has a prevalence ranging from 1 in 700 to 1 in 1,000. We recently reported a susceptibility locus for NSCL/P at chromo some 8q24.21 from a genome wide association study in 224 individuals with NSCL/P (cases) and 383 population based controls 1 . This locus is the second susceptibility locus to have been unequivocally identified for NSCL/P to date, the first being the IRF6 locus 2 .To identify additional cleft susceptibility loci, we enlarged our sample by genotyping an additional set of 177 NSCL/P cases and adding the genotypes of 940 population based controls of central European origin. Genotyping was performed using Illumina BeadChips (Human610 Quad and HumanHap 550k).Following quality control (Supplementary Methods and Supplementary Fig. 1), association analysis of 521,288 SNPs having a minor allele frequency (MAF) of ≥1% in controls was performed in 399 cases and 1,318 controls.After excluding markers from the previously described 8q24.21 locus, 20 SNPs with P < 10 −5 remained. Five chromosomal loci (8q12.3, 10q25.3, 13q31.1, 15q13.3 and 17q22) were located within these 20 top SNPs, and the associations at these loci were further supported by at least three more SNPs with P < 10 −4 ( Supplementary Fig. 2 and Supplementary Table 1). Two additional regions were considered to be promising NSCL/P susceptibility loci (6p22.1, 11q14.2), as they contained at least four markers with P < 10 −4 .To replicate the genome wide association study (GWAS) findings, we selected the 20 top SNPs (P < 10 −5 ) as well as additional backup markers for each of the seven previously mentioned loci, resulting in two replication assays. We included additional SNPs with P < 10 −4 in the two replication assays, giving highest priority to SNPs with the lowest P values. Thus, a total of 56 markers were genotyped in a replication sample of 793 NSCL/P triads of European origin. Genotyping using matrix assisted laser desorption/ionization time of flight (MALDI TOF) mass spectrometry (Sequenom Inc.) was successful for 45 markers (representing 32 different loci), which were then analyzed by the transmission disequilibrium test in 665 triads (128 triads were excluded after quality control, Supplementary Methods).Of the 45 SNPs successfully genotyped, 11 (representing six differ ent loci) showed P < 0.05 in the replication sample (Supplementary Table 2). Two of these SNPs remained significant after correction for multiple testing by a conservative Bonferroni procedure (17q22: rs227731, P corr ...

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; PNSCLP = 6.51 × 10−11; homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84–3.16).

SummaryBackgroundOesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma.MethodsWe did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10−8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches—including functional annotation databases and gene-based and pathway-based methods—to identify pathophysiologically relevant cellular mechanisms.FindingsOur sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10−10), MSRA (rs17749155; p=5·2 × 10−10), LINC00208 and BLK (rs10108511; p=2·1 × 10−9), KHDRBS2 (rs62423175; p=3·0 × 10−9), TPPP and CEP72 (rs9918259; p=3·2 × 10−9), TMOD1 (rs7852462; p=1·5 × 10−8), SATB2 (rs139606545; p=2·0 × 10−8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10−8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10−8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10−6) belonged to muscle cell differentiation and to mesenchyme development and differentiation.InterpretationOur meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might consti...