Additional Susceptibility Loci Research Articles

Meta-Analysis of Genome-Wide Association Studies Identifies Novel Functional CpG-SNPs Associated with Bone Mineral Density at Lumbar Spine.

Osteoporosis is a serious public health issue, which is mostly characterized by low bone mineral density (BMD). To search for additional genetic susceptibility loci underlying BMD variation, an effective strategy is to focus on testing of specific variants with high potential of functional effects. Single nucleotide polymorphisms (SNPs) that introduce or disrupt CpG dinucleotides (CpG-SNPs) may alter DNA methylation levels and thus represent strong candidate functional variants. Here, we performed a targeted GWAS for 63,627 potential functional CpG-SNPs that may affect DNA methylation in bone-related cells, in five independent cohorts (n = 5905). By meta-analysis, 9 CpG-SNPs achieved a genome-wide significance level (p < 7.86 × 10−7) for association with lumbar spine BMD and additional 15 CpG-SNPs showed suggestive significant (p < 5.00 × 10−5) association, of which 2 novel SNPs rs7231498 (NFATC1) and rs7455028 (ESR1) also reached a genome-wide significance level in the joint analysis. Several identified CpG-SNPs were mapped to genes that have not been reported for association with BMD in previous GWAS, such as NEK3 and NFATC1 genes, highlighting the enhanced power of targeted association analysis for identification of novel associations that were missed by traditional GWAS. Interestingly, several genomic regions, such as NEK3 and LRP5 regions, contained multiple significant/suggestive CpG-SNPs for lumbar spine BMD, suggesting that multiple neighboring CpG-SNPs may synergistically mediate the DNA methylation level and gene expression pattern of target genes. Furthermore, functional annotation analyses suggested a strong regulatory potential of the identified BMD-associated CpG-SNPs and a significant enrichment in biological processes associated with protein localization and protein signal transduction. Our results provided novel insights into the genetic basis of BMD variation and highlighted the close connections between genetic and epigenetic mechanisms of complex disease.

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Association Study and Fine-Mapping MajorHistocompatibility Complex Analysisof Pemphigus Vulgaris in aHanChinese Population.

To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P= 3.1× 10-8, odds ratio= 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P= 2.47× 10-38, odds ratio= 6.28), rs7454108 at the TAP2 gene (P= 2.78× 10-12, odds ratio= 3.25), and rs1051336 at the HLA-DRA gene (P= 3.06× 10-6, odds ratio= 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.

841 Association study and fine mapping major histocompatibility complex analysis in pemphigus vulgaris of Han Chinese population

To identify additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed the first genome-wide association study in 240 PV cases and 1,031 controls, and we validated in independent samples of 252 cases and 1,852 controls. We identified rs11218708 (P= 3.1 × 10-8, OR=1.54) at 11q24.1 to be significantly associated with PV. Further fine-mapping analysis of PV risk in the MHC region demonstrated three independent variants predisposed to PV, HLA-DRB1*14:04 (P = 2.47 × 10-38; OR = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12; OR = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10-6; OR = 0.33), by stepwise analysis. A systematic evaluation by gene- and pathway-based analyses demonstrated a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlighted that immune-mediated processes were involved in the pathophysiology of PV and illustrated the value of imputation to identify variants in the MHC region.

MP70-09 IDENTIFICATION OF NINE NEW SUSCEPTIBILITY LOCI FOR PROSTATE CANCER IN THE JAPANESE POPULATION

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2018MP70-09 IDENTIFICATION OF NINE NEW SUSCEPTIBILITY LOCI FOR PROSTATE CANCER IN THE JAPANESE POPULATION Ryo Takata, Shusuke Akamatsu, Hidewaki Nakagawa, Naoki Terada, Yoichiro Kato, Mitsugu Kanehira, Jun Sugimura, So Omori, Takaya Abe, Johji Inazawa, Osamu Ogawa, and Wataru Obara Ryo TakataRyo Takata More articles by this author , Shusuke AkamatsuShusuke Akamatsu More articles by this author , Hidewaki NakagawaHidewaki Nakagawa More articles by this author , Naoki TeradaNaoki Terada More articles by this author , Yoichiro KatoYoichiro Kato More articles by this author , Mitsugu KanehiraMitsugu Kanehira More articles by this author , Jun SugimuraJun Sugimura More articles by this author , So OmoriSo Omori More articles by this author , Takaya AbeTakaya Abe More articles by this author , Johji InazawaJohji Inazawa More articles by this author , Osamu OgawaOsamu Ogawa More articles by this author , and Wataru ObaraWataru Obara More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2253AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer (PC) is one of the most common malignancies in males throughout the world. Although the mechanisms by which prostate cancer develops and progresses are not clear, there is considerable evidence that genetic factors are important in its etiology. Recent genome-wide association studies (GWAS) have identified common variants at multiple loci that have moderate effects on PC risk. However, GWAS for prostate cancer have been undertaken exclusively among European populations. Further GWAS of Asian and other ethnic populations are required to identify additional susceptibility loci for PC and to enhance the understanding of the complex genetic effect on prostate carcinogenesis. To identify genetic factors that confer risk of PC in the Japanese population, we carried out extensive GWAS using Japanese case and controls. METHODS We carried out a genome-wide association study of 511,810 SNPs using 5,088 Japanese men with PC and 10,682 healthy control subjects. We obtained 7,521,072 SNPs information by imputation using 1000 Genomes Project data. In addition, we conducted replication study in an independent set of 4,818 Japanese PC patients and 73,261 control subjects. RESULTS From the 108 associated SNPs reported in previous GWAS, we confirmed the association of 49 SNPs at P < 0.05 in the Japanese population. The remaining 59 SNPs showed no association (P > 0.05). Therefore, it became evident that the SNPs associated with PC pathogenesis greatly varies depending on race. In addition, we performed replication study for 101 SNPs which indicated P < 1.0 x 10-5 in the GWAS. As a result, we identified nine new loci for PC susceptibility at 1p36, 8q24, 10q22, 12p13, 12q21, 15q22, 20p13 and 22q13 (P = 3.34 x 10-8 - 5.28 x 10-20). Moreover, the polymorphisms of SNP and the expression of the surrounding gene showed a significant correlation with QTL analysis in the 2 associated SNPs. CONCLUSIONS This study had an advantage of eliminating of affect for genetic heterogeneity, since we conducted GWAS using genetically quite a homogeneous population of Japanese. These findings advance our understanding of the genetic basis of prostate carcinogenesis and highlight the genetic heterogeneity of PC susceptibility among different ethnic populations. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e937 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Ryo Takata More articles by this author Shusuke Akamatsu More articles by this author Hidewaki Nakagawa More articles by this author Naoki Terada More articles by this author Yoichiro Kato More articles by this author Mitsugu Kanehira More articles by this author Jun Sugimura More articles by this author So Omori More articles by this author Takaya Abe More articles by this author Johji Inazawa More articles by this author Osamu Ogawa More articles by this author Wataru Obara More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Immunochip Meta-Analysis of Inflammatory Bowel Disease Identifies Three Novel Loci and Four Novel Associations in Previously Reported Loci

Recent meta-analysis of genome-wide association studies have identified over 241 inflammatory bowel disease susceptibility loci. However, the known variants only account for a fraction of inflammatory bowel disease heritability. To identify additional susceptibility loci, we performed a trans-ethnic meta-analysis as well as an Asian-specific meta-analysis, using all published Immunochip association results of inflammatory bowel disease. An inverse-variance fixed-effects meta-analysis was carried out across Korean and East Asian Immunochip datasets of 4156 cases and 4904 controls [Asian ancestry]. A trans-ethnic meta-analysis of inflammatory bowel disease was performed together with the European datasets of 38 155 cases and 48 485 controls genotyped on the immunochip using a Bayesian approach, Meta-Analysis of Trans-ethnic Association studies [MANTRA]. We identified seven novel associations, including three novel susceptibility loci at MYO10-BASP1, PPP2R3C/KIAA0391/PSMA6/NFKB1A and LRRK1 as well as four novel secondary associations within previously known loci at NCF4, TSPAN32, CIITA and VANGL2. The new loci further implicate alterations in B cell biology in Crohn's disease pathogenesis. The effects of five loci were universal across European and Asian ancestries, whereas the NCF4 and CIITA loci showed significant heterogeneity between European and East Asian populations. In addition, 103 previously known IBD loci showed supporting evidence of association with nominal significance [p < 0.05] in Asians. Our findings of new loci not previously associated with IBD support the importance of studying inflammatory bowel disease genetics in diverse populations.

Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.

Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD. We performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant (P<5×10-8) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising (P<0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance (P<5×10-8) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci (P<5×10-8) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death. We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD.

Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8+ T-cells and CD4+ T-cells including TH0, TH1 and TH17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10−89). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Effects of RET, NRG1 and NRG3 Polymorphisms in a Chinese Population with Hirschsprung Disease

The RET proto-oncogene was identified as a major locus involved in Hirschsprung disease (HSCR). A genome-wide association study (GWAS) and whole exome sequencing identified NRG1 and NRG3 as additional HSCR susceptibility loci. We investigated the effects of RET (rs2506030 and rs2435357), NRG1 (rs2439302, rs16879552 and rs7835688) and NRG3 (rs10748842, rs10883866 and rs6584400) polymorphisms in a Chinese population with HSCR. We assessed single nucleotide polymorphisms (SNPs) in the RET, NRG1 and NRG3 genes in a cohort of 362 sporadic HSCR patients and 1,448 normal controls using a TaqMan genotyping assay. Significant associations were found between HSCR risk and rs2506030, rs2435357, rs2439302 and rs7835688 (odds ratio [OR] 1.64, P = 1.72E-06; 2.97, P = 5.15E-33; 1.84, P = 9.36E-11; and 1.93, P = 1.88E-12, respectively). Two locus analyses of SNPs indicated increased disease risks of HSCR between NRG1 rs2439302 and RET rs2435357 or rs2506030. RET rs2506030 (GG genotype) and rs2435357 (TT genotype), in combination with NRG1 rs2439302 (GG genotype), were strongly associated with the highest risk of HSCR (OR = 56.53, P = 4.50E-07) compared with the two loci or a single SNP of either RET or NRG1. Our results support the association between genetic variation of RET and NRG1 and susceptibility to HSCR in the Chinese population.

Identification of Two Additional Susceptibility Loci for Inflammatory Bowel Disease in a Chinese Population

Background/Aims: To investigate the associations between the rs1250569 (zinc finger MIZ-type containing 1, ZMIZ1), rs1042522 (tumour protein p53, TP53), and rs10114470 (tumour necrosis factor-like cytokine 1A, TL1A) polymorphisms and the development of inflammatory bowel disease (IBD) in a Chinese (Han) population. We analysed the expression of genes that predispose patients to Crohn’s disease (CD) and ulcerative colitis (UC). Methods: A total of 381 IBD patients and 517 healthy controls were recruited into our study. Polymorphisms at the three loci were genotyped using polymerase chain reaction-ligation detection reactions (PCR-LDR). Genotype-phenotype correlations were analysed. Blood and gut samples were obtained and analysed using quantitative real-time PCR (qRT-PCR), western blot analysis, and immunohistochemistry to investigate the mRNA and protein levels and in situ expression of genes found to predispose patients to IBD. Furthermore, the expression of susceptible genes was further verified using a mouse dextran sulphate sodium (DSS)-induced acute colitis model. Results: No significant association was detected between rs1250569 and rs1042522 genotypes and CD or UC susceptibility. However, the frequency of allele A of rs1250569 was much higher in CD patients than that in healthy controls (55.03% vs. 48.48%, respectively; p = 0.044). The mutation rates at rs10114470 were dramatically lower at both the genotype and allele level in patients than those in healthy controls (p = 0.002 at both the genotype and allele level). Additionally, increased ZMIZ1 and TL1A levels were detected in intestinal samples obtained from both IBD patients and DSS-treated mice. Conclusion: rs1250569 (ZMIZ1) and rs10114470 (TL1A) are two novel loci that indicate susceptibility to IBD in Han-Chinese patients. Consistent with previous studies, TL1A expression levels were higher in Chinese Han IBD patients and DSS-treated mice. Most importantly, we found that ZMIZ1 expression was markedly higher in both IBD patients and mice with experimentally induced colitis, suggesting that ZMIZ1 plays important roles in the pathogenesis of IBD.

Abstract 2568: Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women

Abstract Background: The incidence rates of lung cancer among never-smoking females in some parts of East Asia are among the highest in the world. Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk including 3q28, 5p15.33, 6p21.32, 6q22.2, 10q25.2 and 17q24.3. This study aims to discover additional lung cancer susceptibility loci among never-smoking Asian females. Methods: We imputed data from four GWAS of Asian non-smoking female lung cancer (6,877 cases and 6,277 controls) using the 1,000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5,878 cases and 7,046 controls) for potential replication. Results: In our meta-analysis, three new loci achieved genome-wide significance, marked by the single nucleotide polymorphisms rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10-13), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 ×10-10), and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 ×10-9). Conclusions: We identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia. These findings merit follow-up to understand their biological underpinnings and potential interactions with environmental exposures. Citation Format: Qing Lan, Zhaoming Wang, Wei Jie Seow, Kouya Shiraishi, Hongbing Shen, Chao A. Hsiung, Keitaro Matsuo, Jie Liu, Kexin Chen, Taiki Yamji, Yang Yang, I-Shou Chang, Chen Wu, Meredith Yeager, Takashi Kohno, Wei Zheng, Xiao-Ou Shu, Pan-Chyr Yang, Tangchun Wu, Dongxin Lin, Baosen Zhou, Jinming Yu, Michiaki Kubo, Stephen J. Chanock, Nathaniel Rothman. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2568.

Abstract 2569: A genome wide association study of lung cancer identifies 11 novel susceptibility loci

Abstract Background Genome wide association studies (GWAS) of lung cancer have identified susceptibility loci at 15q25, 5p15, 6p21, 13q13 and 22q12 that contain relevant candidate genes such as CHRNA3/5, TERT, HLA, BRCA2 and CHEK2, respectively. Many of these alleles appear more relevant to a particularly histological type of lung cancer. With the aim of identifying novel lung cancer susceptibility loci, The Transdisciplinary Research in Cancer of the Lung (TRICL), the International Lung Cancer Consortium (ILCCO) and Lung Cancer Cohort Consortium (LC3) have undertaken a very large collaborative GWAS across 29 lung cancer studies, including analysis of the predominant lung cancer histological subtypes. Methods In collaboration with the Center for Disease Research (CIDR), TRICL, ILCCO and LC3 have genotyped 18,000 case-control pairs on the GAME-On Oncoarray. SNP imputation was undertaken using the 1,000 Genomes v3 reference panel, followed by logistic regression of each genetic variant with lung cancer and considering ancestry inferred by genetic profile to correct for cryptic population structure. The OncoArray and our previous GWAS results were combined using meta-analysis. This allowed for a GWAS of 10,155,682 SNPs for 25,655 lung cancer cases and 52,451 controls, as well as histology specific analysis of 6,629 squamous cell and 9,817 adenocarcinomas. Alternate genotyping techniques (Affymetrix, Taqman) were used to confirm the fidelity of the genotyping for variants of interest. Results We have identified common genetic variants exceeding genome wide significance (p&amp;lt;5×10-8) at eleven novel susceptibility loci. This included two associated with overall lung cancer (1p31, 19q13), eight with lung adenocarcinomas (3q28, 6p25, 8p12, 9p21, 10q25, 11q23, 15q21, 20q13) and one with squamous-cell lung carcinomas (10q24). These genetic variants are located near several intriguing candidate genes, such as telomere function genes (OBFC1, RTEL1), nicotine metabolism genes (CYP2A6), genes somatically mutated in lung cancer (NRG1) and genetic susceptibility loci linked to other cancers (IRF4, CDNK2A). In additional, we noted several borderline (p&amp;lt;10-6) associations with common variants located near nicotine addiction genes (CHRNB2, CHRNA2, CHRNA4, DBH) and other genes somatically translocated in lung cancer (ROS1). Integration of eQTL databases suggests that many of the associated genetic variants influence gene expression levels of these candidate genes. Conclusion We have identified eleven novel lung cancer susceptibility loci, doubling the number implicated by GWAS. These genetic variants were common (MAF 0.05-0.49) with modest to small genetic effects (OR's 1.10-1.17). Further expansion of GWAS efforts, particularly within histological subtypes of lung cancer, is likely to identify additional susceptibility loci and further increase our understanding of lung cancer aetiology. Citation Format: James Dowling Mckay, Yafang Li, Younghun Han, Xiangjun Xioa, John Field, Xuchen Zong, Heike Bickeböller, David C. Christiani, Paul Brennan, Maria-Teresa Landi, Rayjean Hung, Christopher I. Amos, on behalf of the OncoArray Lung Cancer Group. A genome wide association study of lung cancer identifies 11 novel susceptibility loci. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2569.

Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis

Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis.

Common genetic variation in ETV6 is associated with colorectal cancer susceptibility.

Genome-wide association studies (GWASs) have identified multiple susceptibility loci for colorectal cancer, but much of heritability remains unexplained. To identify additional susceptibility loci for colorectal cancer, here we perform a GWAS in 1,023 cases and 1,306 controls and replicate the findings in seven independent samples from China, comprising 5,317 cases and 6,887 controls. We find a variant at 12p13.2 associated with colorectal cancer risk (rs2238126 in ETV6, P=2.67 × 10−10). We replicate this association in an additional 1,046 cases and 1,076 controls of European ancestry (P=0.034). The G allele of rs2238126 confers earlier age at onset of colorectal cancer (P=1.98 × 10−6) and reduces the binding affinity of transcriptional enhancer MAX. The mRNA level of ETV6 is significantly lower in colorectal tumours than in paired normal tissues. Our findings highlight the potential importance of genetic variation in ETV6 conferring susceptibility to colorectal cancer.

070 Cyclin D1 promoter -56 and -54 bp CpG un-methylation predicts invasive progression in arsenic-induced Bowen’s disease

1 2 1 1 2 1 1 068 Stat1-dependent senescence is necessary for cancer control during immunotherapy E Brenner , B Schorg , T Wieder , H Braumuller , M Kneilling , J Bauer , K Ghoreschi , A Yazdi and M Rocken 1 Dermatology, Eberhard Karls University, Tubingen, Germany and 2 Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tubingen, Germany Cancer immunotherapies with monoclonal antibodies (mAb) against exhaustion-associated surface molecules, known as immune-checkpoints, reactivate T cells cytotoxic for cancers, and significantly improve survival of patients with various types of cancer. These immunecheckpoint inhibitors are directed against cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1), and disruption of their interactions improves the intermediate-term prognosis even in patients with advanced stage IV melanoma. As the immune system is able to kill tumor cells, it is not astonishing that cancer cell killing has also been demonstrated during immune checkpoint inhibitor therapies. Preclinical data, however, has shown that anti-cancer immunity is not limited to killing cancer cells, and other mechanisms, such as permanent growth arrest or cellular senescence may play an important role as well. Here, we first show that treatment of humans with immune-checkpoint inhibitors induced, besides killing, interferon-dominated type I immunity and senescence in regressing melanoma metastases. To investigate the underlying mechanisms in more detail, we analyzed immune checkpoint inhibitors in advanced solid cancers of RIP1-Tag2 mice, expressing large Tantigen (Tag) under the insulin promoter. Besides partial killing of tumor cells, therapy with immune-checkpoint inhibitors induced type I immunity, a p16/Ki67 senescent phenotype in the remaining cancer cells, and restored long-term survival. In clear contrast, cancers of RIP1-Tag2xSTAT1 mice, deficient in interferon-gsignaling, were resistant to interferon-induced senescence, both in vitro and in vivo. As a consequence, therapy of STAT1-deficient cancers with immune-checkpoint inhibitors in RIP1-Tag2xSTAT1 mice completely failed. Thus, cancer control by immunotherapy with immune-checkpoint inhibitors strictly requires Stat1-dependent cancer cell senescence. 069 Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma HS Chahal, W Wu, K Ransohoff, L Yang, H Hedlin, M Desai, Y Lin, H Dai, AA Qureshi, W Li, P Kraft, D Hinds, J Tang, J Han and K Sarin 1 Dermatology, Stanford School of Medicine, Stanford, CA, 2 Epidemiology, Indiana University, Indianapolis, IN, 3 Medicine (Biostatistics), Stanford University, Stanford, CA, 4 Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China, 5 Dermatology, Brown University, Providence, RI, 6 Epidemiology, Brown University, Providence, RI, 7 Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 8 Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 9 Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA and 10 23andMe Inc., Mountain View, CA Basal cell carcinoma (BCC) is the most common cancer worldwide and contributes substantially to morbidity. Since 2008, 6 population-based genome-wide association studies (GWAS) of BCC have been reported, identifying 16 regions of susceptibility. To identify additional susceptibility loci, we conducted a two-stage GWAS of 17,187 BCC cases and 287,054 controls, making this the largest BCC GWAS to date. The stage 1 set consisted of 12,945 cases and 274,252 controls from the 23andMe research participant cohort, and stage 2 consisted of 4,242 cases and 12,802 controls from the Nurses’ Health/Health Professionals’ cohort. Meta-analysis of the combined data uncovered 14 novel susceptibility loci for BCC reaching genome-wide significance (P<5 10), and also confirmed 12 previously reported associations. These 14 novel loci, some of which are expression quantitative trait loci or keratinocyte regulatory elements, implicate a diverse set of genes—involved in telomere maintenance, immune regulation, and tumor suppression—in BCC susceptibility. Further investigation of these loci will deepen our understanding of BCC pathogenesis and improve our ability to prevent these common tumors.

Abstract P6-18-01: Novel genetic susceptibility loci for inflammatory breast cancer identified by whole exome sequencing

Abstract Background: Inflammatory breast cancer (IBC) is an extremely aggressive form of locally advanced breast cancer that affects approximately 5% of breast cancer patients. The prognosis of IBC patients is remarkably poor, with a three-year survival rate of approximately 30% compared to 60% for non-IBC breast cancer patients. The etiology of IBC is largely unknown. A few risk factors have been reported such as body mass index (BMI) and educational level. Prior evidence has also implicated genetic components in IBC etiology. For instance, the reported familial cases and racial incidence disparity of IBC patients, as well as the fact IBC patients typically have a younger age onset than non-IBC patients, all indicated the possible involvement of genetic factors. Nevertheless, as yet no genetic epidemiological study has been reported to evaluate IBC genetic predisposition. Methods: To test the hypothesis that genetic variants and mutations may affect IBC susceptibility, we performed whole exome sequencing in a pilot case-control study that contained 70 IBC cases and 119 unrelated cancer-free controls. Sequencing data were de-multiplexed, filtered, assessed for various quality control metrics, mapped to reference genome and annotated. Comprehensive single variant-based, gene-centered, and pathway-based analyses were conducted to identify variants, genes, and pathways that may be involved in IBC predisposition. Results: We obtained &amp;gt; 50x on-target sequencing coverage of the whole exome in &amp;gt; 90% of the patients. In single variant analysis, we identified six variants reaching genome-wide significance. Four variants were encoded by genes that have been implicated in breast cancer development including MALAT1, MAP3K9, POLR3B, and FIP1L1. Two variants were encoded by novel genes that have not been related to breast cancer, including CCDC30 and LINC01565. Two types of analyses based on a gene-centered strategy identified top genes such as SLC39A4, CDHR1, AP5Z1, GNB3, ITGA10, etc. However, possibly due to the limited sample size, none of these genes reached genome-wide significance. Ingenuity Pathway Analysis (IPA), using the complete list of significant genes identified by each of these analyses all reported "cancer" as the highest possible disorder associated with these genes, demonstrating the biological plausibility of our findings. Moreover, canonical pathways such as IL4 signaling, glycogen degradation, epithelial adherence junction signaling, and CCR3 signaling in eosinophils were among the top pathways that were found involved in IBC predisposition. Conclusion: Overall, we provided novel preliminary evidence that genetic variants are potentially associated with the risk of developing IBC. We are currently conducting validation studies with larger sample sizes are warranted to confirm these findings and identify additional genetic susceptibility loci. Citation Format: Ye Z, Li B, Wang C, Zhong X, Wei Q, Mu Z, Austin L, Jaslow R, Avery T, Palazzo J, Biederman L, Yang H, Cristofanilli M, IBC Inflammatory Breast Cancer International Consortium. Novel genetic susceptibility loci for inflammatory breast cancer identified by whole exome sequencing. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-18-01.

Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese.

Several genome-wide association studies (GWAS) have demonstrated the association between genetic variants in the major histocompatibility complex (MHC) region and chronic hepatitis B (CHB) virus infection, but it is still unknown about the disease-causing loci and potential mechanisms owing to the complicated linkage disequilibrium for this region. To systematically characterize the MHC variations in relation to the CHB infection, we fine mapped the MHC region on our existing GWAS data with SNP2HLA taken the Pan-Asian panel as reference and finally identified four independent associations. The HLA-DPβ1 amino acid positions 84-87, which drove the effect of reported single nucleotide polymorphisms rs9277535 and rs3077, showed the most significant association (OR = 0.65, P = 2.03 × 10(-8)). The Leu-15 of HLA-C, conferring the effect of rs3130542, increased the risk of CHB infection independently (OR = 1.61, P = 3.42 × 10(-7)). The HLA-DRβ1*13, in perfect LD with glutamic at site 71, and rs400488, an expression quantitative trait locus for HLA-J, were newly identified to be associated with CHB infection independently (OR = 1.84, P = 3.84 × 10(-9); OR = 0.28, P = 6.27 × 10(-7), respectively). HLA-DPβ1 positions 84-87 and HLA-DRβ1 position 71 implicated the P1 and P4 in the antigen-binding groove, whereas HLA-C position 15 affected the signal peptide. These four independent loci together can explain ∼ 6% of the phenotypic variance for CHB infection, accounting for 72.94% of that explained by known genetic variations. We fine mapped the MHC region and identified four loci that independently drove the chronic HBV infection. The results provided a deeper understanding of the GWAS signals and identified additional susceptibility loci which were missed in previous association studies.

Meta-analysis identifies seven susceptibility loci involved in the atopic march.

Eczema often precedes the development of asthma in a disease course called the ‘atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.