Genome-wide analysis of polymorphisms associated with cytokine responses in smallpox vaccine recipients

Kennedy, Richard B.; Ovsyannikova, Inna G.; Pankratz, V. Shane; Haralambieva, Iana H.; Vierkant, Robert A.; Poland, Gregory A.

doi:10.1007/s00439-012-1174-2

Cited by 71 publications

(71 citation statements)

References 64 publications

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“…Rs6813517 is located at 367 kilobase from SPOCK3 , encoding a member of a novel family of calcium-binding proteoglycan proteins, which is strongly expressed in cerebral cortex and hippocampus. Another variant near SPOCK3 (rs13111850, R 2 = .003 with rs6813517) was recently found to be associated with variations in cytokine secretion in response to smallpox vaccine (34). Interestingly, an immune system dysfunction has been suggested in AD based on findings from recent AD GWAS and genome-wide pathway analyses (19,35–37).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Debette

Bressler

et al. 2015

Biological Psychiatry

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BACKGROUND Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

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Section: Discussionmentioning

confidence: 99%

Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Debette

Bressler

et al. 2015

Biological Psychiatry

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“…The phenotype of interest is vaccinia virus-induced IFN-a production detected in peripheral blood mononuclear cells (PBMCs) from first-time recipients of smallpox vaccine. More details about the study cohorts can be found in Ovsyannikova et al (2011Ovsyannikova et al ( , 2012Ovsyannikova et al ( , 2014 and Kennedy et al (2012) gender, time from immunization to blood draw, vaccination date, immune assay batch, and the first principal component to adjust for potential population stratification. For the San Diego cohort, the phenotype was regressed on the following covariates: date of IFN-a assay, date of blood draw, shipping temperature of the sample, site the sample was drawn from, and the second principal component (the first is not included because it is not significant).…”

Section: Application Of Methodsmentioning

confidence: 99%

Fine Mapping Causal Variants with an Approximate Bayesian Method Using Marginal Test Statistics

et al. 2015

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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 ...

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“…(3) This observation might also be because of chance or an unknown biological mechanism. For instance, a GWAS (Kennedy et al, 2012) showed that MAMLD1, 586 kb upstream from the deletion, was associated with immune response to smallpox vaccine; the gamma-aminobutyric acid receptor subunit gene, GABRE, is 851 kb downstream from the deletion.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study of Copy Number Variations (CNVs) with Opioid Dependence

Zhao

Kranzler

et al. 2014

Neuropsychopharmacol

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Single-nucleotide polymorphisms that have been associated with opioid dependence (OD) altogether account for only a small proportion of the known heritability. Most of the genetic risk factors are unknown. Some of the 'missing heritability' might be explained by copy number variations (CNVs) in the human genome. We used Illumina HumanOmni1 arrays to genotype 5152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genome-wide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genome-wide (eg, P ¼ 2 Â 10 À 8 and OR (95% CI) ¼ 0.64 (0.54-0.74) for a chromosome 18q12.3 deletion). Several rare or unique CNVs showed suggestive or marginal significance with large effect sizes. This study is the first GWAS of OD using CNVs. Some identified CNVs harbor genes newly identified here to be of biological importance in addiction, whereas others affect genes previously known to contribute to substance dependence risk. Our findings augment our specific knowledge of the importance of genomic variation in addictive disorders, and provide an addiction CNV pool for further research. These findings require replication.

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Genome-wide analysis of polymorphisms associated with cytokine responses in smallpox vaccine recipients

Cited by 71 publications

References 64 publications

Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Fine Mapping Causal Variants with an Approximate Bayesian Method Using Marginal Test Statistics

Genome-Wide Association Study of Copy Number Variations (CNVs) with Opioid Dependence

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