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Dale Nyholt and colleagues report a genome-wide association meta-analysis of endometriosis in individuals of Japanese and European ancestry. They report a new susceptibility locus at 12q22 and establish an association at 2p25.1. We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese 1 and European 2 ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese ( P = 3.6 × 10 −3 ), and we confirm association of rs7521902 at 1p36.12 near WNT4 . In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 × 10 −8 in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent ( P = 8.8 × 10 −11 ), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations.

Chlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in the WDR92 (eQTL for PPP3R1 ) was significantly associated with better DBP response to CTD (p = 5.76 × 10 −6 , β = −15.75) in the AA cohort. This SNP further replicated in PEAR (p = 0.00046, β = −9.815) with a genome wide significant meta-analysis p-value of 8.49 × 10 −9 . This variant was further validated for opposite association in two β-blockers treated cohorts from PEAR-2 metoprolol (p = 9.9 × 10 −3 , β = 7.47) and PEAR atenolol (p = 0.04, β = 4.36) for association with DBP. Studies have implicated WDR92 in coronary artery damage. PPP3R1 is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms in PPP3R1 to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest that WDR92 and PPP3R1 are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to β-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.

Alison Klein and colleagues report a genome-wide meta-analysis to identify loci associated with pancreatic cancer risk. They identify associated variants at 17q25.1, 3q29, 7p13 and 2p13.3. Pancreatic cancer is the fourth leading cause of cancer death in the developed world 1 . Both inherited high-penetrance mutations in BRCA2 (ref. 2 ), ATM 3 , PALB2 (ref. 4 ), BRCA1 (ref. 5 ), STK11 (ref. 6 ), CDKN2A 7 and mismatch-repair genes 8 and low-penetrance loci are associated with increased risk 9 , 10 , 11 , 12 . To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 ( LINC00673 , rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19–1.34, P = 1.42 × 10 −14 ), 7p13 ( SUGCT , rs17688601, OR = 0.88, 95% CI = 0.84–0.92, P = 1.41 × 10 −8 ) and 3q29 ( TP63 , rs9854771, OR = 0.89, 95% CI = 0.85–0.93, P = 2.35 × 10 −8 ). We detected significant association at 2p13.3 ( ETAA1 , rs1486134, OR = 1.14, 95% CI = 1.09–1.19, P = 3.36 × 10 −9 ), a region with previous suggestive evidence in Han Chinese 12 . We replicated previously reported associations at 9q34.2 ( ABO ) 9 , 13q22.1 ( KLF5 ) 10 , 5p15.33 ( TERT and CLPTM1 ) 10 , 11 , 13q12.2 ( PDX1 ) 11 , 1q32.1 ( NR5A2 ) 10 , 7q32.3 ( LINC-PINT ) 11 , 16q23.1 ( BCAR1 ) 11 and 22q12.1 ( ZNRF3 ) 11 . Our study identifies new loci associated with pancreatic cancer risk.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved. Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al . identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

Patrick Concannon and colleagues present a type 1 diabetes genome-wide association study and meta-analysis in 7,514 cases and 9,045 reference samples, reporting 22 newly identified loci. Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis ( P < 10 −6 ). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated ( P < 0.01; overall P < 5 × 10 −8 ) and 4 additional regions provided nominal evidence of replication ( P < 0.05). The many new candidate genes suggested by these results include IL10 , IL19 , IL20 , GLIS3 , CD69 and IL27 .

Zi-Jiang Chen and Yongyong Shi report a genome-wide association study for polycystic ovary syndrome, a common metabolic and endocrine disorder in women. They identified three susceptibility loci associated with this condition. Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women. To identify causative genes, we conducted a genome-wide association study (GWAS) of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved two independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). We identified strong evidence of associations between PCOS and three loci: 2p16.3 (rs13405728; combined P -value by meta-analysis P meta = 7.55 × 10 −21 , odds ratio (OR) 0.71); 2p21 (rs13429458, P meta = 1.73 × 10 −23 , OR 0.67); and 9q33.3 (rs2479106, P meta = 8.12 × 10 −19 , OR 1.34). These findings provide new insight into the pathogenesis of PCOS. Follow-up studies of the candidate genes in these regions are recommended.

Markus Schürks and colleagues report a genome-wide association study for common migraine. They identify three new susceptibility loci at PRDM16 , TRPM8 and LRP1 . Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16 ), rs10166942 (2q37.1, TRPM8 ) and rs11172113 (12q13.3, LRP1 ) were among the top seven associations ( P < 5 × 10 −6 ) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10 −9 ; rs10166942, OR = 0.85, P = 5.5 × 10 −12 ; and rs11172113, OR = 0.90, P = 4.3 × 10 −9 ). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Richard Lifton and colleagues report the identification of three susceptibility loci for intracranial aneurysm. Two of the loci are new, with SNPs on chromosome 8q likely acting through SOX17 , which is required for the formation and maintenance of endothelial cells. Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects ∼2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment 1 . The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24–1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm 2 , 3 , 4 , 5 . Associated SNPs on 8q likely act via SOX17 , which is required for formation and maintenance of endothelial cells 6 , 7 , 8 , suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role 9 . These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Using the technique of genomewide association analysis, the authors found a locus on chromosome 9 (9p21.3) that is strongly associated with familial coronary artery disease. The precise gene that may be involved is not known and will require further study, but this type of genomic analysis is likely to lead to a deeper understanding of the pathogenesis of coronary artery disease and other chronic diseases. Using the technique of genomewide association analysis, the authors found a locus on chromosome 9 that is strongly associated with familial coronary artery disease. Coronary artery disease and its main complication, myocardial infarction, are leading causes of death and disability worldwide. 1 Lifestyle and environmental factors play an important role in their development. 2 In addition, these complex diseases cluster in families, suggesting a substantial genetic cause. 3 Despite extensive exploration of many genes, strong evidence of a molecular genetic association with coronary artery disease or myocardial infarction remains to be obtained. The recent development of high-density genotyping arrays provides unprecedented resolution for whole-genome assessment of variants associated with common diseases. 4 Using the GeneChip Human Mapping 500K Array Set (Affymetrix), which simultaneously types approximately 500,000 genetic variants, . . .

Montserrat Garcia-Closas and colleagues report a genome-wide association study for bladder cancer. They identify three new susceptibility loci on chromosomes 22q13.1, 19q12 and 2q37.1. We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, ( P = 8 × 10 −12 ) maps to a non-genic region of chromosome 22q13.1, rs8102137 ( P = 2 × 10 −11 ) on 19q12 maps to CCNE1 and rs11892031 ( P = 1 × 10 −7 ) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion ( P = 4 × 10 −11 ) and a tag SNP for NAT2 acetylation status ( P = 4 × 10 −11 ), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.