Genomic screening in family-based association testing and the multiple testing problem

in Genetic Epidemiology. Supplement (2005), 28

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of ... [more ▼]

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome- wide family- based association studies, using single SNPs or haplotypes, can identify associations that achieve genome- wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease- susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease- susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype- tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome- wide significance, as population- based designs do. [less ▲]

PBAT: a comprehensive software package for genome-wide association analysis of complex family-based studies

in Human Genomics (2005), 2(1), 67-9

The PBAT software package (v2.5) provides a unique set of tools for complex family-based association analysis at a genome-wide level. PBAT can handle nuclear families with missing parental genotypes ... [more ▼]

The PBAT software package (v2.5) provides a unique set of tools for complex family-based association analysis at a genome-wide level. PBAT can handle nuclear families with missing parental genotypes, extended pedigrees with missing genotypic information, analysis of single nucleotide polymorphisms (SNPs), haplotype analysis, quantitative traits, multivariate/longitudinal data and time to onset phenotypes. The data analysis can be adjusted for covariates and gene/environment interactions. Haplotype-based features include sliding windows and the reconstruction of the haplotypes of the probands. PBAT's screening tools allow the user successfully to handle the multiple comparisons problem at a genome-wide level, even for 100,000 SNPs and more. Moreover, PBAT is computationally fast. A genome scan of 300,000 SNPs in 2,000 trios takes 4 central processing unit (CPU)-days. PBAT is available for Linux, Sun Solaris and Windows XP. [less ▲]

Genomic screening and replication using the same data set in family-based association testing

in Nature Genetics (2005), 37(7), 683-691

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of ... [more ▼]

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome- wide family- based association studies, using single SNPs or haplotypes, can identify associations that achieve genome- wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease- susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease- susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype- tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome- wide significance, as population- based designs do. [less ▲]

Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q

in American Journal of Human Genetics (2005), 77(4), 582-95

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is ... [more ▼]

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches. [less ▲]

Genomic screening in family-based association testing

in BMC Genetics (2005), 6

Due to the recent gains in the availability of single-nucleotide polymorphism data, genome-wide association testing has become feasible. It is hoped that this additional data may confirm the presence of ... [more ▼]

Due to the recent gains in the availability of single-nucleotide polymorphism data, genome-wide association testing has become feasible. It is hoped that this additional data may confirm the presence of disease susceptibility loci, and identify new genetic determinants of disease. However, the problem of multiple comparisons threatens to diminish any potential gains from this newly available data. To circumvent the multiple comparisons issue, we utilize a recently developed screening technique using family-based association testing. This screening methodology allows for the identification of the most promising single-nucleotide polymorphisms for testing without biasing the nominal significance level of our test statistic. We compare the results of our screening technique across univariate and multivariate family-based association tests. From our analyses, we observe that the screening technique, applied to different settings, is fairly consistent in identifying optimal markers for testing. One of the identified markers, TSC0047225, was significantly associated with both the ttth1 (p=0.004) and ttth1-ttth4 (p=0.004) phenotype(s). We find that both univariate- and multivariate-based screening techniques are powerful tools for detecting an association. [less ▲]

Genomic screening and replication in one data set in family-based association testing

in Conference Abstract Book (2005)

On missing phenotype data in multivariate family based association tests: FBAT-GEE-IMP and imputation strategies based on the EM-algorithm, the DA-algorithm and the conditional mean model

in Far East J. Theo. Stat. (2004), 13(2), 175-188

Genomic screening in family-based association testing

in Genetic Epidemiology (2004), 27