Two recently developed fine-mapping methods, CAVIAR and PAINTOR, demonstrate better performance over other finemapping methods. They also have the advantage of using only the marginal test statistics and the correlation among SNPs. Both methods leverage the fact that the marginal test statistics asymptotically follow a multivariate normal distribution and are likelihood based. However, their relationship with Bayesian fine mapping, such as BIMBAM, is not clear. In this study, we first show that CAVIAR and BIMBAM are actually approximately equivalent to each other. This leads to a fine-mapping method using marginal test statistics in the Bayesian framework, which we call CAVIAR Bayes factor (CAVIARBF). Another advantage of the Bayesian framework is that it can answer both association and fine-mapping questions. We also used simulations to compare CAVIARBF with other methods under different numbers of causal variants. The results showed that both CAVIARBF and BIMBAM have better performance than PAINTOR and other methods. Compared to BIMBAM, CAVIARBF has the advantage of using only marginal test statistics and takes about one-quarter to onefifth of the running time. We applied different methods on two independent cohorts of the same phenotype. Results showed that CAVIARBF, BIMBAM, and PAINTOR selected the same top 3 SNPs; however, CAVIARBF and BIMBAM had better consistency in selecting the top 10 ranked SNPs between the two cohorts. Software is available at https://bitbucket.org/Wenan/caviarbf. KEYWORDS Bayesian fine mapping; marginal test statistics; causal variants U NTIL recently, there have been .2000 genome-wide association studies (GWAS) published with different traits or disease status (Hindorff et al. 2014). Most of them reported only regions of association, represented by SNPs with the lowest P-values in each region. Only a few provide further information of likely underlying causal variants. A noted exception is refinement based on Bayesian methods (Maller et al. 2012). Fine mapping the causal variants from the verified association regions is an important step toward understanding the complex biological mechanisms linking the genetic code to various traits or phenotypes.Fine-mapping methods can be roughly divided into two groups. The first group was developed before the availability of high-density genotype data. These fine-mapping methods assume the causal variants are not genotyped in the data and aim to identify a region as close as possible to the causal variants (Morris et al. 2002; Durrant et al. 2004;Liang and Chiu 2005;Zollner and Pritchard 2005;Minichiello and Durbin 2006;Waldron et al. 2006). Because the causal variants are not observed in the data, these methods usually rely on various strong assumptions to model the relationship of the causal and the observed variants. Examples include models based on the coalescent theory (Morris et al. 2002;Zollner and Pritchard 2005;Minichiello and Durbin 2006) or statistical assumptions about the patterns of linkage disequilibrium (LD) (Liang and ...

Background Population-based studies have revealed 2 to 10% measles vaccine failure rate even after two vaccine doses. While the mechanisms behind this remain unknown, we hypothesized that host genetic factors are likely to be involved. Methods We performed a genome-wide association study of measles specific neutralizing antibody and IFNγ ELISPOT response in a combined sample of 2,872 subjects. Results We identified two distinct chromosome 1 regions (previously associated with MMR-related febrile seizures), associated with vaccine-induced measles neutralizing antibody titers. The 1q32 region contained 20 significant SNPs in/around the measles virus receptor-encoding CD46 gene, including the intronic rs2724384 (p-value = 2.64x10−09) and rs2724374 (p-value = 3.16x10−09) SNPs. The 1q31.1 region contained nine significant SNPs in/around IFI44L, including the intronic rs1333973 (p-value = 1.41x10−10) and the missense rs273259 (His73Arg, p-value = 2.87x10−10) SNPs. Analysis of differential exon usage with mRNA-Seq data and RT-PCR suggests the involvement of rs2724374 minor G allele in the CD46 STP region exon B skipping, resulting in shorter CD46 isoforms. Conclusions Our study reveals common CD46 and IFI44L SNPs associated with measles-specific humoral immunity, and highlights the importance of alternative splicing/virus cellular receptor isoform usage as a mechanism explaining inter-individual variation in immune response after live measles vaccine.

Genetic pleiotropy is when a single gene influences more than one trait. Detecting pleiotropy and understanding its causes can improve the biological understanding of a gene in multiple ways, yet current multivariate methods to evaluate pleiotropy test the null hypothesis that none of the traits are associated with a variant; departures from the null could be driven by just one associated trait. A formal test of pleiotropy should assume a null hypothesis that one or no traits are associated with a genetic variant. For the special case of two traits, one can construct this null hypothesis based on the intersection-union (IU) test, which rejects the null hypothesis only if the null hypotheses of no association for both traits are rejected. To allow for more than two traits, we developed a new likelihood-ratio test for pleiotropy. We then extended the testing framework to a sequential approach to test the null hypothesis that [Formula: see text] traits are associated, given that the null of k traits are associated was rejected. This provides a formal testing framework to determine the number of traits associated with a genetic variant, while accounting for correlations among the traits. By simulations, we illustrate the type I error rate and power of our new methods; describe how they are influenced by sample size, the number of traits, and the trait correlations; and apply the new methods to multivariate immune phenotypes in response to smallpox vaccination. Our new approach provides a quantitative assessment of pleiotropy, enhancing current analytic practice.

Obesity is a risk factor for complicated influenza A/H1N1 disease and poor vaccine immunogenicity. Leptin, an adipocyte-derived hormone/cytokine, has many immune regulatory functions and therefore could explain susceptibility to infections and poor vaccine outcomes. We recruited 159 healthy adults (5074 years old) who were immunized with inactivated TIV influenza vacci–ne that contained A/California/7/2009/H1N1 virus. We found a strong correlation between leptin concentration and BMI (r=0.55, p<0.0001), but no association with hemagglutination antibody inhibition (HAI), B-cell, or granzyme B responses. We found a slight correlation between leptin concentration and an immunosenescence marker (TREC: T-cell receptor excision circles) level (r=0.23, p=0.01). We found eight SNPs in the LEP/LEPR/GHRL genes that were associated with leptin levels and four SNPs in the PTPN1/LEPR/STAT3 genes associated with peripheral blood TREC levels (p<0.05). Heterozygosity of the synonymous variant rs2230604 in the PTPN1 gene was associated with a significantly lower (531 vs. 259, p = 0.005) TREC level, as compared to the homozygous major variant. We also found eight SNPs in the LEP/PPARG/CRP genes associated with variations in influenza-specific HAI and B-cell responses (p<0.05). Our results suggest that specific allelic variations in the leptin-related genes may influence adaptive immune responses to influenza vaccine.

We assessed the effects of sex, race and ethnicity on smallpox vaccine-induced immune responses in 1,071 armed forces members after primary Dryvax® smallpox vaccination, including 790 males and 281 females; 580 Caucasians, 217 African-Americans, and 217 Hispanics. Analysis of vaccinia-specific cytokine responses revealed that Caucasians had higher total IFNγ ELISPOT responses (median 57 spot-forming units/SFUs per 200,000 cells, p=0.01) and CD8+IFNγ ELISPOT responses (12 SFUs, p<0.001) than African-Americans (51 and 4 SFUs, respectively) and Hispanics (47 and 8 SFUs, respectively). Similarly, Caucasians secreted higher levels of vaccinia-specific IL-2 (p=0.003) and IFNα (p<0.001) compared to other racial/ethnic groups. Males had higher total IFNγ ELISPOT responses (median 55 SFUs) compared to females (41 SFUs, p<0.001). We observed statistically significant sex-related differences in the secretion of IL-2 (p<0.001), IL-1β (p<0.001) and IL-10 (p=0.017). These data suggest that vaccinia-specific cytokine responses following primary smallpox vaccination are significantly influenced by race and sex of vaccinees.