Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.     

Common 5p15.33 and 6p21.33 variants influence lung cancer risk

We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 x 10(-12)), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; P(combined) = 4.97 x 10(-10)) and 5p15.33 (rs401681, CLPTM1L; P(combined) = 7.90 x 10(-9)).     

Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci

We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 (IL2-IL21, P = 1.9 x 10(-8)) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 x 10(-12)), 10p15 (PRKCQ, P = 3.7 x 10(-9)), 15q24 (CTSH, P = 3.2 x 10(-15)) and 22q13 (C1QTNF6, P = 2.0 x 10(-8)).     

Discovery of common variants associated with low TSH levels and thyroid cancer risk

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10(-8) in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; P(combined) = 1.3 × 10(-9)), rs2439302 on 8p12 (OR = 1.36; P(combined) = 2.0 × 10(-9)) and rs116909374 on 14q13.3 (OR = 2.09; P(combined) = 4.6 × 10(-11)), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10(-91)) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.     

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population

To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS) of lung cancer in the Chinese population in an extended validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10(-8)) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10(-10)), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10(-9)) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10(-8)). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10(-8)) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10(-6)). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10(-10), P = 5.07 × 10(-3), P = 6.77 × 10(-3) and P = 4.49 × 10(-2) for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer.     

Genome-wide association analysis identifies three new breast cancer susceptibility loci

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ～8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ～70,000 cases and ～68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.     

A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese

Lung cancer is the leading cause of cancer-related deaths worldwide. To identify genetic factors that modify the risk of lung cancer in individuals of Chinese ancestry, we performed a genome-wide association scan in 5,408 subjects (2,331 individuals with lung cancer (cases) and 3,077 controls) followed by a two-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10(-8)) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10(-26)), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10(-20) and P = 1.0 × 10(-27), respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10(-12)) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10(-11) and P = 6.2 × 10(-13), respectively). Two of these loci (13q12.12 and 22q12.2) were newly identified in the Chinese population. These results suggest that genetic variants in 3q28, 5p15.33, 13q12.12 and 22q12.2 may contribute to the susceptibility of lung cancer in Han Chinese.     

A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.     

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献   

Common variants at 6q22 and 17q21 are associated with intracranial volume

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.     

Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13

The WTCCC study identified 49 SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-4) - 1 x 10(-5) (tier 3). Here we show that three of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend P = 4 x 10(-5), P = 4 x 10(-4) and P = 4 x 10(-4), respectively) in a validation study of 4,106 individuals with rheumatoid arthritis and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in individuals of European ancestry.     

Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population

Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87 × 10(-12)), a locus on chromosome 10p14 (P = 1.79 × 10(-15)) and a gene-rich region on chromosome 12q13 (P = 2.33 × 10(-13)). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07 × 10(-23)), which is close to rs2070600, a SNP previously reported for association with FEV(1)/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility.     

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.     

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer

We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).     

SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 x 10(-12); OR = 1.26, 95% CI = 1.18-1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 x 10(-9); OR = 1.32, 95% CI = 1.20-1.45, rs2237897, P = 6.8 x 10(-13); OR = 1.41, 95% CI = 1.29-1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 x 10(-3); OR = 1.14, rs2237897, P = 2.4 x 10(-4); OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 x 10(-11); OR = 1.24, rs2237897, P = 1.2 x 10(-4); OR = 1.36).     

A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population

Through a genome-wide association analysis with a total of 7,035 individuals with duodenal ulcer and 25,323 controls from Japan, we identified two susceptibility loci at the PSCA gene (encoding prostate stem cell antigen) at 8q24 and at the ABO blood group locus at 9q34. The C allele of rs2294008 at PSCA was associated with increased risk of duodenal ulcer (odds ratio (OR) = 1.84; P = 3.92 × 10(-33)) in a recessive model but was associated with decreased risk of gastric cancer (OR = 0.79; P = 6.79 × 10(-12)), as reported previously. The T allele of rs2294008 encodes a translation initiation codon upstream of the reported site and changes protein localization from the cytoplasm to the cell surface. rs505922 at ABO was also associated with duodenal ulcer in a recessive model (OR = 1.32; P = 1.15 × 10(-10)). Our findings demonstrate a role for genetic variants in the pathogenesis of duodenal ulcer.     

Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis

Infantile hypertrophic pyloric stenosis (IHPS) is a severe condition characterized by hypertrophy of the pyloric sphincter muscle. We conducted a genome-wide association study (GWAS) on 1,001 surgery-confirmed cases and 2,401 controls from Denmark. The six most strongly associated loci were tested in a replication set of 796 cases and 876 controls. Three SNPs reached genome-wide significance. One of these SNPs, rs11712066 (odds ratio (OR) = 1.61; P = 1.5 × 10(-17)) at 3p25.1, is located 150 kb upstream of MBNL1, which encodes a factor that regulates splicing transitions occurring shortly after birth. The second SNP, rs573872 (OR = 1.41; P = 4.3 × 10(-12)), maps to an intergenic region at 3p25.2 approximately 1.3 Mb downstream of MBNL1. The third SNP, rs29784 (OR = 1.42; P = 1.5 × 10(-15)) at 5q35.2, is 64 kb downstream of NKX2-5, which is involved in development of cardiac muscle tissue and embryonic gut development.     

A genome-wide association study identifies three new risk loci for Kawasaki disease

We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.