Breast cancer risk is influenced by rare coding variants in susceptibility genes such as BRCA1 and many common, mainly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. We report results from a genome-wide association study (GWAS) of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci associated with overall breast cancer at p<5x10-8. The majority of credible risk SNPs in the new loci fall in distal regulatory elements, and by integrating in-silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all SNPs in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the utility of genetic risk scores for individualized screening and prevention.

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Obesity is a risk factor for a wide variety of health problems. In a genome-wide association study (GWAS) of body mass index (BMI) in Japanese people (n = 173,430), we found 85 loci significantly associated with obesity (P < 5.0 × 10), of which 51 were previously unknown. We conducted trans-ancestral meta-analyses by integrating these results with the results from a GWAS of Europeans and identified 61 additional new loci. In total, this study identifies 112 novel loci, doubling the number of previously known BMI-associated loci. By annotating associated variants with cell-type-specific regulatory marks, we found enrichment of variants in CD19 cells. We also found significant genetic correlations between BMI and lymphocyte count (P = 6.46 × 10, r = 0.18) and between BMI and multiple complex diseases. These findings provide genetic evidence that lymphocytes are relevant to body weight regulation and offer insights into the pathogenesis of obesity.

The impact of metabolic factors, which are major risk factors for cardiovascular disease, on total cancer risk has not been clarified. We prospectively examined whether metabolic factors and their aggregates predict the subsequent occurrence of total and major sites of cancer in the Japan Public Health Center-based Prospective Study. A total of 27 724 participants (9548 men and 18 176 women) aged 40-69 years participating in a questionnaire and health checkup survey in 1993-1995 were followed for total cancer incidence through 2004. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for metabolic factors and for two criteria of their aggregates (three or more than three factors and two or more than two additional factors in addition to being overweight) with a Cox proportional hazards model to control for potential confounding factors. In both sexes, the presence of metabolic factors in the aggregate did not predict subsequent occurrence of cancer as a whole. By site, a significant increase in risk was observed for male liver cancer [HR = 1.73, CI = 1.03-2.91 (three or more than three factors); HR = 1.99, CI = 1.11-3.58 (two or more than two additional factors in addition to being overweight)], and female pancreatic cancer [HR = 1.99, CI = 1.00-3.96 (two or more than two additional factors in addition to being overweight)]. For other sites, positive associations were observed only for specific metabolic factors, that is, high triglycerides and male colon cancer (HR = 1.71, CI = 1.11-2.62), and obesity and female breast cancer (HR = 1.75, CI = 1.21-2.55). Metabolic factors in the aggregate may have little impact on total cancer risk in the Japanese population, although the association between specific components and specific cancers suggests an etiologic link between them.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 14% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.