Haplotype Reference Consortium Panel Research Articles

Genome-wide association study (GWAS) and novel prognostic markers in metastatic colorectal cancer (mCRC).

174 Background: Few genome-wide investigations have examined germline variants associated with mCRC outcomes following primary treatment. Here, we performed a GWAS meta-analysis to explore the impact of germline genetic variation on progression-free survival (PFS) and overall survival (OS) in four clinical trials of mCRC. Methods: The GWAS comprised 1,324 mCRC patients (pts) enrolled in four randomized Phase II/III trials for first line treatment: FIRE-3 (FOLFIRI-bevacizumab [bev]; FOLFIRI-cetuximab[cet]), MAVERICC (FOLFIRI-bev; FOLFOX6-bev), TRIBE (FOLFIRI-bev; FOLFOXIRI-bev), and TRIBE2 (mFOLFOX6-bev; FOLFOXIRI-bev). DNA isolated from blood was genotyped using the OncoArray and imputed against the Haplotype Reference Consortium panel. In each trial arm, associations between SNPs and PFS and OS were assessed using an additive coding in a Cox proportional hazard framework, adjusting for trial specific patient characteristics and principal components. Meta-analysis was carried out using an inverse-variance weighted fixed effect model. All reported GWAS p-values were adjusted for genomic inflation. To further investigate significant hits, we evaluated associations between gene expression measured from FFPE tumor samples and PFS and OS in 433 pts enrolled in an independent randomized first-line Phase III trial, CALGB/SWOG 80405. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in multivariable Cox models for expression levels in the top (Q4, high) vs the bottom quartile (Q1, low). Results: Two SNPs in the MLPH intronic region and one SNP in the TYR intronic region surpassed the GWAS significance threshold for PFS and OS, respectively. The top ranked SNPs associated with PFS and OS, rs13409241 (A>G, PFS HR: 1.35, 95% CI [1.21, 1.51], P=4.34E-8) and rs10765199 (T>A, OS HR: 1.45, 95%CI [1.27, 1.65], P=4.69E-8), showed similar effects across all eight treatment arms ( I2 = 0% and 38.5%, respectively). No significant heterogeneity variant was found. In the CALGB/SWOG 80405 cohort, pts with MLPH-low tumors (N=109) showed significantly longer PFS (median 14.8 vs 7.6 months, low vs. high (as reference) adjusted HR 0.53, 95% CI [0.38, 0.74], P=2.1E-4) and OS (median 35.8 vs. 18.2 months, adjusted HR 0.65, 95% CI [0.46, 0.92], P=0.015) compared to MLPH-high (N=107). No significant associations for TYR expression and outcomes were found. MLPH and TYR are involved in melanosome transport and melanogenesis. Melanin has been shown to reduce vitamin D levels, which can affect CRC prognosis. MLPH has also been reported to accelerate epithelial-mesenchymal transition and metastasis in lung and prostate cancers. Conclusions: These results suggest that germline genetic variation in MLPH and TYR may affect mCRC prognosis via a mechanism that involves melanin and possibly the epithelial-mesenchymal transition. Note: Authors Millstein and Lenz contributed equally to this work.

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation.

The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

Assessing a Network‐Specific Polygenic Risk Score for Alzheimer’s Disease in the Midwestern Amish and Across Diverse Ancestries

AbstractBackgroundAlzheimer’s disease (AD), the most common type of dementia, has a complex etiology with a strong genetic component. Many genetic risk variants for AD have been identified including APOE, the largest known genetic risk factor. However, most of this research has examined only broad populations of individuals with European ancestry and there is mounting evidence that effect sizes vary by population. Here, we investigate the transferability of polygenic risk scores (PRSs), including a network‐specific PRS, in the midwestern Amish and across diverse ancestries.MethodData from 1,091 Amish adults with AD diagnosis by consensus were considered for analysis from the Collaborative Amish Aging & Memory Project. Genotype data (Illumina GSA and MEGAEX) were imputed using the Haplotype Reference Consortium panel. We also analyzed 15,745 individuals from the Alzheimer’s Disease Sequencing Project (ADSP) r3 with three predominant race/ethnicity groups: African American (AA; n=2,937), Hispanic (n=3,047), and non‐Hispanic White (NHW; n=9,708). An AD network‐specific PRS was constructed by including variants from AD‐implicated molecular networks in the Kyoto Encyclopedia of Genes and Genomes. A comprehensive pruning and thresholding PRS considering all variants was calculated for comparison. Effect estimates from Kunkle et al. (2019) were used. PRS‐only models, sex and age covariate‐only, and full models were constructed for each group and the full ADSP data.ResultWe observed that PRS‐only predictive ability was similar between the comprehensive PRS (AUC=0.56) and the network‐specific PRS (AUC=0.55) in the full ADSP r3 data. Network‐specific PRS performance was similar in the Amish (AUC=0.55). However, we observed better predictive ability with the comprehensive PRS compared to the network‐specific PRS in each of the subgroups (Amish AUC: 0.61 vs. 0.55; NHW: 0.70 vs. 0.53; AA: 0.56 vs. 0.53, Hispanic: 0.61 vs. 0.56). These trends were consistent after inclusion of sex and age covariates.ConclusionWe demonstrated that a network‐specific PRS performed similarly to a comprehensive PRS in a combined diverse population and the Amish but confers less predictive ability when investigating individual subgroups. Thus, the network‐specific PRS has potential as a component of a risk model in diverse populations because it may successfully account for effects that are consistent across subgroups.

Abstract 2002: A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group

Abstract Background: Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL) and are more likely to experience morbidity and mortality from infectious toxicities during treatment compared to those without DS. We sought to characterize genetic risk factors for sepsis among individuals with DS-ALL. Methods: We performed a germline genome-wide association (GWAS) study for sepsis among 264 subjects with DS-ALL treated on Children’s Oncology Group (COG) protocols AALL0932 (N=181) and AALL1131 (N=83), for newly-diagnosed standard risk and high risk B-ALL, respectively. Sepsis was defined using Common Terminology Criteria for Adverse Events (v4.0), with a microbiologically confirmed grade 4 or 5 sepsis event reported during any phase of treatment to define the case and comparison groups. Germline genotyping on the Affymetrix SNP 6.0 or Illumina Omni 2.5Exome arrays was imputed to the Haplotype Reference Consortium panel and filtered for quality control. Logistic regression models were used to compare individuals with DS-ALL who experienced sepsis to those who never developed sepsis during treatment. Models were adjusted for principal components of population structure and COG protocol. Analyses included autosomal variants with a minor allele frequency >1% and excluded chromosome 21. Results: We identified 29 individuals (10.9%) with DS-ALL who developed one or more sepsis events during treatment. In genome-wide analyses, we observed 52 variants in eight genomic loci associated with sepsis at P<10-5 among individuals with DS-ALL. Our top signal was rs77917748 (P=6.02x10-7), an intronic variant in a regulatory region of TMEM163, a protein that is essential for zinc homeostasis. Additionally, we identified a strong linkage signal at rs56288508 on chr6p21.2 (P=5.29x10-6). According to data from the Genotype-Tissue Expression (GTEx) project, this locus is associated with whole blood expression of ZFAND3, a zinc finger protein and transcriptional regulator. Additionally, this variant is associated with intestinal infections (P=0.012) in the UK Biobank. Finally, a third variant we identified in our GWAS is on chr6q24.2 (P=4.33x10-6) and shows strong linkage in GTEx with peripheral blood mononuclear cell expression of APOBEC3A, a viral deaminase that lacks zinc binding activity. Notably, this variant is associated with respiratory failure (P=0.0099) in the UK Biobank. Conclusion: We identified evidence of genetic associations for sepsis risk in DS-ALL. These findings suggest zinc homeostasis may be an important factor mediating risk of sepsis during treatment of individuals with DS-ALL. Confirmatory studies and validation in additional cohorts are ongoing. Citation Format: Melissa A. Richard, Meenakshi Devidas, Wenjian Yang, John P. Woodhouse, Vilmarie Rodriguez, Johann K. Hitzler, Reuven J. Schore, Anne L. Angiolillo, Michael J. Burke, Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2002.

Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema.

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.

Abstract 820: NSAIDs and colorectal cancer risk: Results from genome-wide interaction scans

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) are consistently shown in epidemiological and clinical studies to exert chemo-preventive effects on colorectal cancer (CRC). Specifically, aspirin binds irreversibly to COX1/2 enzymes, attenuating pro-inflammatory signaling pathways, but it can also exert protective effects via Wnt-β-catenin signaling, circulating inflammatory cytokines, and platelet mediated mechanisms. In this analysis, we conduct genome-wide interaction scans on a large CRC dataset to expand upon previous work and identify novel G x NSAIDs interactions. We pooled epidemiological and imputed genetic data from 72,667 individuals (41,876 controls, and 30,806 cases) of European descent from 31 studies. Genotypes were imputed to the Haplotype Reference Consortium panel. Regular use of aspirin and combined aspirin/non-aspirin NSAIDs (henceforth termed ‘nsaidsALL') were harmonized across studies and measured as ever/never at reference time. We employed several statistical methods in our GWIS: traditional logistic regression with an interaction term, case-only analyses, joint tests (2df/3df), two-step methods. We also assessed interactions between CRC polygenic risk scores (PRS) and aspirin/nsaidsALL on additive and multiplicative scales. PRS was modeled categorically (quartiles) and continuously as a per 1 SD increase from the minimum value. All models were adjusted for age, sex, study, and ancestry. Aspirin (OR=0.789, 95% CI=0.753-0.826) and nsaidsALL (OR=0.760; 95% CI=0.726-0.793) use were inversely associated with CRC risk. Using standard logistic regression, we identified a genome-wide significant interaction between rs72833769 (chromosome 6 intergenic region upstream of PHACTR1) and both aspirin and nsaidsALL (p = 4.0e-09, p = 1.3e-08, respectively). An additional genome-wide interaction locus was identified for nsaidsALL only, on rs35118762 (p = 2.2e-08), located in the Major Histocompatibility Complex region and in close linkage with a previously identified marginal GWAS hit (rs9271695). We identified another region of interest using two-step methods tagged by SNP rs350047 (aspirin pgxe = 1.1e-05, nsaidsALL pgxe = 4.4e-05). This region also coincides with another previously identified marginal GWAS hit (rs12514517), and is notable for being upstream of PTGER4, an important receptor for aspirin mediated inflammatory response signaling. For interactions with PRS, we observed a significant super-additive interaction for both aspirin (RERI=0.102, p=7e-08) and nsaidsALL use (RERI=0.132, p=4.6e-12). Results were similar when modeling PRS categorically. There were no multiplicative scale interactions between PRS and any NSAID use. GWIS for aspirin and nsaidsALL use identified several loci of interest that warrant follow-up in functional studies. Citation Format: Andre E. Kim, David A. Drew, Yi Lin, Conghui Qu, John P. Morrison, Stephanie Bien, Victor Moreno, Graham Casey, Ulrike Peters, Andrew T. Chan, W James Gauderman. NSAIDs and colorectal cancer risk: Results from genome-wide interaction scans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 820.

Abstract 824: Germline genetic regulation of the adaptive immune response in colorectal cancer

Abstract Adaptive immune responses in the tumor microenvironment of colorectal cancer (CRC) play an important role in prognosis. However, the contributions of germline genetic variations to the strength and diversity of T cell responses in CRC are unclear. We conducted a genome-wide association study to examine the relationships between germline genetic variants and measures of the T cell repertoire in colorectal tumors. Germline DNA samples from 5,581 CRC cases recruited into the Molecular Epidemiology of Colorectal Cancer Study (MECC) were genotyped in batches using four different platforms. Genotype data were imputed to the Haplotype Reference Consortium panel separately by genotyping platform. Tumor DNA samples were extracted from paraffin blocks, and tumor infiltrating lymphocytes per high powered field (TILs/hpf) were quantified by a single gastrointestinal pathologist. TCR abundance and clonality within individual CRCs were measured using the immunoSEQ assay (Adaptive Biotechnologies). Appropriate quality control steps and data transformations were applied to fit downstream statistical modeling assumptions. After standard quality control on both imputed genotypes and transformed immune metrics, 2,876 (TILs/hpf) and 2,395 (TCR abundance and clonality) cases with approximately 9 million imputed genetic variants were included in the discovery phase. Logistic or linear regression models were used to evaluate the associations between allelic dosage of each variant and each immune-related outcome, adjusting for sex, age at diagnosis, genotyping platform, and principal components for global ancestry. Three independent datasets were available to replicate our findings using similar quality control measures and regression models: Colonomics (N=96; TILs/hpf, TCR abundance, clonality), the CRC Genetics Study (N=162; TCR abundance, clonality), and the Harvard Cohorts (N=505; TILs/hpf; in progress). The discovery phase identified 5 independent genetic variants associated with TILs/hpf, 15 associated with TCR abundance, and 19 associated with clonality at p&amp;lt;5X10E-06. Replication analyses as well as expression quantitative trait analyses and in silico functional annotation are underway for the loci of interest. Our study suggests that germline genetic variation is associated with the quantity and quality of adaptive immune responses in CRC. Citation Format: Stephanie L. Schmit, Ya-Yu Tsai, Joseph Bonner, Rebeca Sanz-Pamplona, Amit D. Joshi, Sidney S. Lindsey, Marilena Melas, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Tomotaka Ugai, Hedy S. Rennert, Harlan S. Robins, Joel K. Greenson, Shuji Ogino, Victor Moreno, Gad Rennert, Stephen B. Gruber. Germline genetic regulation of the adaptive immune response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 824.

Genome-Wide Association Study for Waldenström Macroglobulinemia Identifies Novel Susceptibility Loci

Waldenström macroglobulinemia (WM) is a unique subset of lymphoplasmacytic lymphoma (LPL) that is defined by the presence of an LPL infiltrate in the bone marrow together with a monoclonal IgM protein in the serum. Family history is strongly associated with risk of WM, and the estimated heritability is high; however, the genetic basis for WM predisposition remains unknown. To identify susceptibility loci for WM, we conducted a two-stage genome-wide association study (GWAS) in over 500 WM/LPL cases and 4300 controls of European ancestry. In the discovery stage (stage 1), 217 unrelated WM cases (40% familial) and 3,798 controls were genotyped on the Illumina Omni Express or Illumina Omni2.5 platforms. After quality control filtering, the data were imputed using the Haplotype Reference Consortium panel and analyzed using logistic regression. Eleven promising loci (P <5.0 x 10-7) were selected for replication in 313 WM/LPL cases and 564 controls. Two novel loci were convincingly replicated in stage 2 (P<1.2 x 10-5) and reached genome-wide significance in the combined analysis of both stages: 6p25.3 (EXOC2, OR=21.14, P=1.36 x 10-54) and 14q32.13 (intergenic near TCL1, OR=4.90, P=8.74 x 10-19). A possible second independent signal was observed at 14q32.13 but did not reach genome-wide significance (P=4.66 x 10-7). When the analysis was limited to WM, results were slightly stronger but generally similar to those for WM/LPL combined. Dysregulated TCL1 expression in B cells enhances cell proliferation and survival, leading to cell transformation and mature B-cell tumors, and TCL1 has been shown to be aberrantly expressed in WM. EXOC2 interacts with Ral proteins to mediate oncogenic RAS signaling that is critical for cancer cell survival and proliferation. We found that cells transduced with the EXOC2 variant allele reporter pCS-EGFP-3'G showed significantly increased EGFP fluorescence compared to the wildtype, suggesting the variant is associated with increased EXOC2 protein levels. Cells harboring the EXOC2 variant allele were also observed to have significantly increased cell proliferation compared to wildtype cells. We further discovered that the E XOC2 variant abrogates a miRNA binding site, possibly contributing to gene expression changes for NF-κB pathway constituents. Together these newly discovered loci explain ~4% of the familial risk and suggest possible underlying biological mechanisms, significantly increasing our understanding of the genetic susceptibility of WM/LPL. DisclosuresCerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering .

Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer\u2019s disease

Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

Association Between Collagenous and Lymphocytic Colitis and Risk of Severe Coronavirus Disease 2019

Association Between Collagenous and Lymphocytic Colitis and Risk of Severe Coronavirus Disease 2019

TopMed‐imputed genome‐wide association study of Alzheimer’s disease in more than 100,000 European samples from the EADB project

AbstractBackgroundGenome‐wide association studies (GWAS), and more recently the next‐generation sequencing strategy, improved greatly our knowledge of the genetics of Alzheimer’s disease (AD), with more than 40 risk genes/loci now identified. As part of the genetic component of AD remains unknown, we conducted a complementary GWAS study with increased sample size and improved imputation quality of low frequency variants thanks to the new TopMed imputation panel.MethodThe GWAS was performed in the European Alzheimer DNA Biobank (EADB) dataset. It combines genome‐wide genotyping data from several studies and from more than 18,000 AD cases and 21,000 controls never included in previous AD discovery GWAS, for a total of more than 35,000 AD cases and 65,000 controls of European ancestry. Imputation was performed with the TopMed reference panel for the majority of the samples or with the Haplotype Reference Consortium panel. Variants with imputation quality below 0.3 were excluded. Logistic regressions were performed in each study with adjustment on principal components and results were combined across studies with a fixed‐effect inverse variance meta‐analysis.ResultPreliminary association results were available for 27,752,571 variants following quality control, including 8,633,349 common variants (minor allele frequency (MAF) above 1%), and 1,324,211 low frequency variants (MAF range between 0.5% and 1%). We identified 57 loci with at least suggestive evidence (P &lt; 1 × 10−6) of association, including 31 known AD loci. Among the 26 new loci, 10 loci reached genome‐wide significance (P &lt; 5 × 10−8) and 9 loci had a rare lead variant (MAF below 1%).ConclusionPreliminary results of the EADB project allowed to identify several new associated loci for AD, including several good candidate genes linked to the APP metabolism. Additional insights on the genetics of AD are expected from ongoing analyses, including gene‐based tests of rare variants, fine‐mapping, functional annotations and pathway analyses.

Abstract 1194: Cross-cancer GWAS meta-analysis of more than 370,000 cases and 530,000 controls identifies multiple novel cancer risk regions

Abstract Genome-wide association studies (GWAS) have identified hundreds of common, low-penetrance alleles associated with cancer risk. However, known rare and common risk alleles only explain between 10% and 30% of the familial relative risk for different cancers and multiple lines of evidence indicate that many more risk alleles remain to be discovered. We have demonstrated genetic correlations between cancers, reflecting a shared genetic origin for solid tumors. These results suggest that jointly analyzing multiple cancer sites will lead to the discovery of novel risk regions. We conducted a cross-cancer GWAS meta-analysis by leveraging GWAS summary statistics from 12 solid cancers (breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate and renal cancers) with a total of 373,818 cases and 532,382 controls of European ancestry. All studies had been imputed to either 1,000 Genomes or the Haplotype Reference Consortium panel. We conducted four meta-analysis using (1) fixed-effect, (2) random-effect, (3) one-sided subset (ASSET) and (4) two-sided subset (ASSET) models. The subset analysis were conducted assuming either the same direction of effects across cancers (one-sided ASSET) or allowed for opposite direction of effects across cancers (two-sided ASSET). In all analyses, we used tetrachoric correlations to account for sample overlap across cancer sites. In total, we tested 10,223,013 variants for association. We considered regions with a p-value&amp;lt;1.25 × 10−8 in at least one of the four meta-analysis approaches and located at least 500kb away from known cancer risk SNPs as novel. We identified eight novel regions that reached genome-wide significance. Of those eight regions, two were identified from fixed-effects meta-analysis, three from random effects meta-analysis, one from the two-sided subset analysis, and two regions (15.q15.3 and 21q22.3) were identified at p&amp;lt;1.25 × 10−8 in three of the meta-analysis approaches. Among novel findings is a deleterious missense variant located in RREB1 previously associated with type 2 diabetes, a deleterious missense variant located in DSTYK previously associated with waist-to-hip ratio and triglycerides, and an intergenic variant in linkage disequilibrium (LD) with variants in TMEM18, previously associated with body mass index. Other potential target genes among the newly discovered regions include TP53BP1 and PCNT, both previously implicated in carcinogenesis. Citation Format: Sara Lindström, Siddhartha Kar, Lu Wang, Constance Turman, James MacDonald, Theo Bammler, BCAC, OCAC, PRACTICAL, Jeroen Huyghe, Stephanie Schmit, Tracy A. O'Mara, Deborah J. Thompson, Puya Gharahkhani, Stuart MacGregor, Paul Brennan, Richard S. Houlston, Beatrice S. Melin, Christopher I. Amos, James McKay, Mark M. Iles, Matthew H. Law, Alison Klein, Laufey Amundadottir, Bogdan Pasaniuc, Paul Pharoah, Rayjean J. Hung, Peter Kraft. Cross-cancer GWAS meta-analysis of more than 370,000 cases and 530,000 controls identifies multiple novel cancer risk regions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1194.

Association of asthma and its genetic predisposition with the risk of severe COVID-19

Summary In a large population-based cohort data, adults with asthma had a higher risk of severe COVID-19, which was driven by the increased risk among patients with non-allergic asthma.

Abstract C048: Multiethnic polygenic risk scores and smoking interactions for chronic obstructive lung disease

Abstract Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US with differential risk across race/ethnicity groups and increases lung cancer risk. In the Multiethnic Cohort (MEC), an ethnically diverse prospective cohort (&amp;gt;215,000) established in the early 1990’s in California and Hawaii, we found COPD prevalence was highest in African Americans, followed by European Americans, Native Hawaiians, Latinos and Japanese Americans. Family history and smoking are strong risk factors for COPD with heritability estimates ranging from 20-40%. However, large scale genomic studies (GWAS) have primarily focused on Europeans. Thus, ethnic-specific calibration of polygenic risk scores (PRS) for predicting COPD has the potential to identify those with greatest need for recommended screening and targeted prevention. Methods: Incident COPD case status was identified from linkage to Medicare claims files which followed a total of 17,291 for PRS analyses from 1998-2014. We performed Cox regression accounting for pack-years smoked and duration quit at two time points of 3,917 COPD cases with genetic data. Genotyped data from MEC individuals from multiple SNP arrays were imputed to the Haplotype Reference Consortium panel (~39 million SNPs). From this repository, we extracted 82 independent risk loci identified from the largest (250,000 European individuals) lung function/COPD GWAS to date from the UK Biobank. To calculate the COPD PRS, we matched imputed dosages to the 82 reported UK Biobank risk allele by locus and summed MEC genotypes under a standard additive general linear model. We compared two Cox regression models 1) not including PRS and 2) including PRS. Results: From epidemiologic analysis, we find that smoking is highly predictive of COPD risk (as expected) and that even after adjusting for pack-years of smoking and years quit racial disparities are evident, with African Americans (Hazard Ratio (HR): 1.25, p=3.7 × 10−6) and Japanese Americans (HR: 1.14, p=0.017) having slightly increased risk of disease compared to European Americans; whereas, Native Hawaiians have similar risk as European Americans (HR=0.95, p=0.48) and Latinos have decreased risk (HR: 0.75, p=2.43 × 10−8). Testing the PRS, we found an 8% increase risk per standard deviation (HR:1.08, p=5.41 × 10−6) while ethnic group differences in risk remained quite similar after adjustment for the PRS. Testing for interaction between pack-years and PRS, we found a suggestive increase of the smoking effect for those with the highest levels of PRS (p=0.09). Conclusion: Based on the racial disparities present from our COPD findings, particularly the increased risks among African Americans and Japanese Americans, we will examine the excess relative risk over a lifetime and within 5-year age intervals. We are currently expanding our MEC genotyped repository which should double our sample size, improve ability to detect PRS-smoking interactions, as well as test PRS for lung cancer. Citation Format: Linda M. Polfus, Meng Lin, S. Lani Park, David Conti, Jackie Porcel, Veronica W. Setiawan, Lynne Wilkens, Christopher A. Haiman, Loïc Le Marchand, Daniel O. Stram. Multiethnic polygenic risk scores and smoking interactions for chronic obstructive lung disease [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C048.

P20 The identification of novel genetic susceptibility loci for juvenile idiopathic arthritis by analysis across clinical subgroups

Abstract Background Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of childhood onset inflammatory joint diseases with strong evidence to support a genetic contribution to susceptibility. JIA is divided into seven clinical subgroups based on observed patterns of clinical symptoms using the International League of Associations for Rheumatology (ILAR) classification system. The genetic overlap between these groups is not completely understood and this lack of knowledge typically leads to the different ILAR groups being analysed as discrete entities potentially reducing the power of genetic association studies. The aim of this study was to conduct a large case-control association study on susceptibility to JIA to identify novel susceptibility loci and to investigate differences in these associations between the different ILAR groups for the purposes of maximising power. Methods JIA participants were genotyped on the Illumina Infinium CoreExome or OmniExpress arrays. UK population control genotype data was obtained from the Understanding Society Longitudinal Study. Quality control of data was performed conforming to conventional standards and imputation was performed using the Haplotype Reference Consortium panel on the Michigan Imputation Server. Association testing of all SNPs was performed with an additive model incorporating imputation uncertainty using SNPTEST. Testing for specificity and sharing across ILAR groups was performed using Bayesian multinomial regression in the Trinculo software package. Loci passing the suggestive significance threshold (5x10-6) were selected for meta-analysis with previously published JIA GWAS data assuming fixed effects and weighted by inverse-variance using the software package GWAMA. Results Following quality control the dataset consisted of &amp;gt; 7.4 million SNPs for 3305 JIA cases and 9196 controls. We found no strong evidence to support association of any SNP to a specific ILAR group with most of the SNPs showing evidence for sharing across multiple groups. Association testing in a combined dataset of all ILAR groups identified seven SNPs associated at genome-wide significance (5x10-8); six of these have previously been reported for JIA while one is a novel association. The novel association (rs497523, p-value = 7.12x10-9) maps to chromosome 16p11 and is located within intron one of the CCDC101 gene. Meta-analysis identified association to rs7647909 which is an intronic variant in the FOXP1 gene (p-value 2.0x10-9) and rs2614258 within the AHI1 gene (p-value 9.5x10-12). Conclusion We identified novel associations to SNPs in the CCDC101 and FOXP1 genes. In addition, we report a genome-wide significant association to AHI1, previously reported at suggestive significance levels. Fine mapping with the integration of genomic data will be required to identify the true causal gene at each of these loci. The results provide little evidence to support ILAR subgroup specificity for any of the associated variants and combined analysis of data across subgroups maximised power to identify novel associations. Disclosures J. Bowes None. M.C. Marion None. S. Smith None. A. Yarwood None. M. Sudman None. D. Tarasek None. C.D. Langefeld None. S.D. Thompson None. W. Thomson None.

Genotype imputation and reference panel: a systematic evaluation on haplotype size and diversity.

Here, 622 imputations were conducted with 394 customized reference panels for Han Chinese and European populations. Besides validating the fact that imputation accuracy could always benefit from the increased panel size when the reference panel was population specific, the results brought two new thoughts. First, when the haplotype size of the reference panel was fixed, the imputation accuracy of common and low-frequency variants (Minor Allele Frequency (MAF) > 0.5%) decreased while the population diversity of the reference panel increased, but for rare variants (MAF < 0.5%), a small fraction of diversity in panel could improve imputation accuracy. Second, when the haplotype size of the reference panel was increased with extra population-diverse samples, the imputation accuracy of common variants (MAF > 5%) for the European population could always benefit from the expanding sample size. However, for the Han Chinese population, the accuracy of all imputed variants reached the highest when reference panel contained a fraction of an extra diverse sample (8-21%). In addition, we evaluated the imputation performances in the existing reference panels, such as the Haplotype Reference Consortium (HRC), 1000 Genomes Project Phase 3 and the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE). For the European population, the HRC panel showed the best performance in our analysis. For the Han Chinese population, we proposed an optimum imputation reference panel constituent ratio if researchers would like to customize their own sequenced reference panel, but a high-quality and large-scale Chinese reference panel was still needed. Our findings could be generalized to the other populations with conservative genome; a tool was provided to investigate other populations of interest (https://github.com/Abyss-bai/reference-panel-reconstruction).

P06 Genetics of juvenile idiopathic arthritis: the identification of a novel risk locus and clinical subgroup analysis

Poster presentation Tuesday 8 October Background Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of childhood onset inflammatory joint diseases with strong evidence to support a genetic contribution to susceptibility. JIA is divided into seven clinical subgroups based on observed patterns of clinical symptoms using the International League of Associations for Rheumatology (ILAR) classification system. The genetic overlap between these groups is not completely understood and this lack of knowledge typically leads to the different ILAR groups being analysed as discrete entities and reducing the overall power of genetic association studies. The aim of this study was to conduct a large case-control association study on susceptibility to JIA to identify novel susceptibility loci and to investigate differences in these associations between the different ILAR groups. Methods JIA participants were genotyped on the Illumina Infinium CoreExome or OmniExpress arrays at the University of Manchester. UK population control genotype data was obtained from the Understanding Society Longitudinal Study. Quality control of data was performed conforming to conventional standards based on call rate, cryptic relatedness and ancestry outliers. Imputation was performed using the Haplotype Reference Consortium panel on the Michigan Imputation Server followed by exclusion of SNPs with low imputation accuracy (r2 &lt; 0.5) and low minor allele frequency (&lt; 1%). Association testing of all SNPs was performed with an additive model incorporating imputation uncertainty using SNPTEST. A subset of SNPs independently associated with all JIA (p-value &lt; 5x10-6) were tested to evaluate if they were specific to a particular ILAR group or shared across multiple ILAR groups using Bayesian multinomial regression and model selection methods implemented in the Trinculo software package. Results Following quality control, the dataset consisted of &gt; 7.4 million SNPs for 3,305 JIA cases and 9,196 controls. Association testing in a combined dataset of all ILAR groups identified seven SNPs associated at genome-wide significance (5x10-8); six of these have previously been reported for JIA while one is a novel association. The novel association (rs497523, p-value = 7.12x10-9, OR 0.85, 95% CI 0.8:0.9) maps to chromosome 16p11 and is located within intron one of the CCDC101 gene. In a subset of 44 independently associated SNPs we found no strong evidence to support association of any SNP to a specific ILAR group with the majority of the SNPs showing evidence for sharing across multiple groups. Conclusion In a large case control association study for susceptibility to JIA, we identified a novel association to a SNP in the intron of CCDC101. This gene is involved in transcriptional regulation through histone acetyltransferase. The results support a general model of sharing of loci across multiple ILAR groups. The combined analysis of data across subgroups, informed by model sharing, will maximise power to identify novel associations. Conflicts of Interest The authors declare no conflicts of interest.

Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival.

BackgroundThe incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.MethodsWe tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10−8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.FindingsCarrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10−9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10−9, and this was replicated, OR = 3.4 [95% CI 1.2–9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.InterpretationWe found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

SU110 - ROLE OF 108 SCHIZOPHRENIA-ASSOCIATED LOCI IN MODULATING PSYCHOPATOLOGICAL DIMENSIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER

Background Schizophrenia is a highly heritable disorder and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) identified 108 loci with genome-wide association with broad schizophrenia diagnosis. Schizophrenia is a clinically complex entity and the role of these 108 loci in modulating specific clinical features of the disease is still unknown. This study investigated which symptom dimensions may be affected by these loci in schizophrenia and bipolar disorder. Methods Positive, negative and depressive symptoms, suicidal ideation, cognition, violent behaviors, quality of life and early onset were investigated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) samples. Only white subjects were included to avoid possible confounding from ancestry stratification. Imputation of genotypes was carried out after standard quality control using the Haplotype Reference Consortium panel as reference. Individual loci were investigated using linear or logistic regression, then genes within 50 Kbp from polymorphisms with p Results 89 polymorphisms among the 108 of interest were available in both samples, 479 and 810 white subjects were included from CATIE and STEP-BD, respectively. rs75059851 (IGSF9B gene) was associated with negative symptoms in CATIE (p=0.00048); no other variants survived after multiple-testing correction. rs1023500 (CENPM gene) showed a trend of association with early onset with consistent direction in both samples (p=0.033 in STEP-BD and p=0.073 in CATIE). GeneMania analysis showed that negative symptoms and suicidal ideation had a relevant enrichment of Gene Ontology (GO) terms related to acetylcholine neurotransmission, monoamines and ion channel activity while pyridoxal phosphate binding and fucose metabolism showed enrichment for cognition. GO terms referred to processes involved in extracellular matrix structure were found enriched for early onset. PRS showed nominal associations with violent behaviors (p=0.034, Nagelkerke's R2=0.014) and depressive symptoms (p=0.04, R2=0.009). Discussion This study provided preliminary evidence that a schizophrenia-associated variant in the IGSF9B (immunoglobulin superfamily member 9B) gene may modulate negative symptoms. IGSF9B is involved in GABAergic signaling and it may mediate negative symptoms by affecting depression and cognition. A polymorphism in the CENPM (centromere protein M) gene showed an interesting trend of association with early onset. CENPM encodes for an inner protein of the kinetochore, the multi-protein complex that binds spindle microtubules to regulate chromosome segregation during cell division. Multi-locus models may provide interesting insights about the biological mechanisms that medicate specific symptom domains and the genetic overlap between schizophrenia and bipolar disorder.

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P<5×10−8, bringing the number of known independent signals for CRC to approximately 100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs, somatic drivers, and support a role of immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of underlying biology, and impact personalized screening strategies and drug development.