Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Summary statistic analyses do not correct confounding bias

LD SCore regression (LDSC) has become a popular approach to estimate confounding bias, heritability and genetic correlation using only genome wide association study (GWAS) test statistics. SumHer is a newly-introduced alternative with similar aims. We show using theory and simulations that both approaches fail to adequately account for confounding bias, even when the assumed heritability model is correct. Consequently, these methods may estimate heritability poorly if there was inadequate adjustment for confounding in the original GWAS analysis. We also show that choice of summary statistic for use in LDSC or SumHer can have a large impact on resulting inferences. Further, covariate adjustments in the original GWAS can alter the target of heritability estimation, which can be problematic when LDSC or SumHer is applied to test statistics from a meta-analysis of GWAS with different covariate adjustments.

Abstract MP60: Investigation of Blood Pressure Genetic Loci in African Americans using the Metabochip

Introduction. African Americans (AA) have a higher burden of hypertension than European descent individuals, thus motivating research on blood pressure (BP) risk factors in AA, including genetic variants. Yet to date, few genome-wide association studies (GWAS) of BP have been conducted in AA and it is unclear whether genetic variants identified in mainly European descent populations are also associated with BP in AA. Furthermore, investigation of established BP loci in diverse race/ethnicity groups such as AA, who tend to have higher levels of genetic diversity, provides opportunities to narrow loci for identifying potential causal variants. Methods. We examined whether systolic BP (SBP) and diastolic BP (DBP) loci on the Illumina Metabochip array were associated with BP traits in 18,832 AA from the PAGE, HyperGen and GenNet studies. Only SNPs with minor allele frequency≥0.001 and passing stringent QC were tested. Using p-value<0.05 as a significance threshold for replication of GWAS SNPs in our AA population, we investigated the original GWAS SNP and all SNPs ±500 kilobases in modest linkage disequilibrium with it (r 2 ≥0.3). To test SNPs in the 16 SBP and 14 DBP loci, we used a Bonferroni corrected p-value of 0.05/total SNPs per locus (the number SNPs at each BP locus ranges from 104 to 2,337). Results. In models adjusted for sex, age, body mass index and global ancestry, 5 prior GWAS SNPs were associated (p<0.05) with DBP: rs13107325/ SLC39A8 (non-synonymous), rs1165196/ SLC17A1 (non-synonymous), rs6495122/ CPLX3 , rs1327235/intergenic and rs6015450/intergenic. At several loci, we identified finely-mapped SNPs more strongly associated with DBP in AA than the original GWAS SNPs. Notably, we identified rs56153133 in the gene-rich 1p26 region harboring the chloride channel-voltage-sensitive-6 ( CLCN6 ) gene, p=6.9E-5. This SNP is highly correlated with the GWAS SNP rs17367504/ MTHFR in European-descent individuals (r 2 =0.98) and less so in AA (r 2 =0.64). For SBP, we replicated two GWAS SNPs: rs16998073/intergenic and rs2681472/ ATP2B1 and at many loci (10q24, 1p26, 15q26 et al .), we identified SNPs more strongly associated with SBP in AA than the original GWAS SNPs. Conclusions. Overall, several BP loci originally reported in individuals of European and East Asian ancestry also generalize to AA, which confirms the relevance of specific BP susceptibility loci across diverse populations. In addition, we identified SNPs more strongly associated with BP traits in AA than the original GWAS SNPs, underlying the importance of leveraging differences in nucleotide diversity and LD patterns among populations to narrow GWAS signal boundaries. Future work will include conditional analysis to further refine GWAS loci, and to identify additional signals and population-specific variation.