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Vitamin D is postulated to decrease the risk of breast cancer by inhibiting cell proliferation via the vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNPs) in the VDR gene, rs1544410 (BsmI) and rs2228570 (FokI), are inconsistently associated with breast cancer risk in Caucasian populations, while data for Asians are scarce. Here, we investigated the possible contribution of these SNPs to breast cancer risk in Pakistani breast cancer patients and in controls participating in a hospital-based breast cancer case-control study (PAK-BCCC). Genotyping of the BsmI and FokI SNPs was performed by PCR-based restriction fragment length polymorphism (RFLP) analysis of 463 genetically enriched female breast cancer cases with known BRCA1/2 status and in 1,012 controls from Pakistan. The association between SNP genotypes and breast cancer risk was investigated by logistic regression adjusted for potential breast cancer risk factors and stratified by BRCA1/2 status and family history. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. The b allele of the BsmI was associated with an increased breast cancer risk (per b allele OR 1.28, 95% CI 1.09-1.49, P = 0.003). Subgroup analysis revealed that this effect was restricted to BRCA1/2 non-carriers (per b allele OR 1.33, 95% CI 1.11-1.59, P = 0.002) and was stronger in those who reported a positive family history of breast and/or ovarian cancer (per b allele OR 1.64, 95% CI 1.20-2.22, P = 0.002). No association with breast cancer risk was detected for the FokI SNP. The BsmI polymorphism in the VDR gene may be associated with an increased breast cancer risk in Pakistani women negative for BRCA1/2 germline mutations.

Background Genotypes not directly measured in genetic studies are often imputed to improve statistical power and to increase mapping resolution. The accuracy of standard imputation techniques strongly depends on the similarity of linkage disequilibrium (LD) patterns in the study and reference populations. Here we develop a novel approach for genotype imputation in low-recombination regions that relies on the coalescent and permits to explicitly account for population demographic factors. To test the new method, study and reference haplotypes were simulated and gene trees were inferred under the basic coalescent and also considering population growth and structure. The reference haplotypes that first coalesced with study haplotypes were used as templates for genotype imputation. Computer simulations were complemented with the analysis of real data. Genotype concordance rates were used to compare the accuracies of coalescent-based and standard ( IMPUTE2 ) imputation. Results Simulations revealed that, in LD-blocks, imputation accuracy relying on the basic coalescent was higher and less variable than with IMPUTE2 . Explicit consideration of population growth and structure, even if present, did not practically improve accuracy. The advantage of coalescent-based over standard imputation increased with the minor allele frequency and it decreased with population stratification. Results based on real data indicated that, even in low-recombination regions, further research is needed to incorporate recombination in coalescence inference, in particular for studies with genetically diverse and admixed individuals. Conclusions To exploit the full potential of coalescent-based methods for the imputation of missing genotypes in genetic studies, further methodological research is needed to reduce computer time, to take into account recombination, and to implement these methods in user-friendly computer programs. Here we provide reproducible code which takes advantage of publicly available software to facilitate further developments in the field.

Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss. We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/m2 or more. We randomly assigned participants (6:1) to each active treatment group (ie, semaglutide [0·05 mg, 0·1 mg, 0·2 mg, 0·3 mg, or 0·4 mg; initiated at 0·05 mg per day and incrementally escalated every 4 weeks] or liraglutide [3·0 mg; initiated at 0·6 mg per day and escalated by 0·6 mg per week]) or matching placebo group (equal injection volume and escalation schedule to active treatment group) using a block size of 56. All treatment doses were delivered once-daily via subcutaneous injections. Participants and investigators were masked to the assigned study treatment but not the target dose. The primary endpoint was percentage weight loss at week 52. The primary analysis was done using intention-to-treat ANCOVA estimation with missing data derived from the placebo pool. This study is registered with ClinicalTrials.gov, number NCT02453711. Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102–103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/m2. Bodyweight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was −2·3% for the placebo group versus −6·0% (0·05 mg), −8·6% (0·1 mg), −11·6% (0·2 mg), −11·2% (0·3 mg), and −13·8% (0·4 mg) for the semaglutide groups. All semaglutide groups versus placebo were significant (unadjusted p≤0·0010), and remained significant after adjustment for multiple testing (p≤0·0055). Mean bodyweight reductions for 0·2 mg or more of semaglutide versus liraglutide were all significant (−13·8% to −11·2% vs −7·8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37–65% receiving 0·1 mg or more of semaglutide (p<0·0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists. In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses. Novo Nordisk A/S.

Doug Easton and colleagues report the results of a large-scale genome-wide association study of breast cancer. They discover 15 new susceptibility loci and highlight likely target genes in several of the newly associated regions. Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10 −8 . Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1 .

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response. Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10 −14 ), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Genotypes not directly measured in genetic studies are often imputed to improve statistical power and to increase mapping resolution. The accuracy of standard imputation techniques strongly depends on the similarity of linkage disequilibrium (LD) patterns in the study and reference populations. Here we develop a novel approach for genotype imputation in low-recombination regions that relies on the coalescent and permits to explicitly account for population demographic factors. Simulations revealed that, in LD-blocks, imputation accuracy relying on the basic coalescent was higher and less variable than with IMPUTE2. Explicit consideration of population growth and structure, even if present, did not practically improve accuracy. The advantage of coalescent-based over standard imputation increased with the minor allele frequency and it decreased with population stratification. Results based on real data indicated that, even in low-recombination regions, further research is needed to incorporate recombination in coalescence inference, in particular for studies with genetically diverse and admixed individuals. To exploit the full potential of coalescent-based methods for the imputation of missing genotypes in genetic studies, further methodological research is needed to reduce computer time, to take into account recombination, and to implement these methods in user-friendly computer programs. Here we provide reproducible code which takes advantage of publicly available software to facilitate further developments in the field.

Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

BackgroundBRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.MethodsWe evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.ResultsThe rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).ConclusionsThese results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Background Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. Methods To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Results Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P  < 5.0x10 -8 . Conclusion In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.