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A unified framework for multi-locus association analysis of both common and rare variants.

Shriner D, Vaughan LK - BMC Genomics (2011)

Bottom Line: We identified a single risk haplotype with a directionally consistent effect in both samples in the gene GAK, which is involved in clathrin-mediated membrane trafficking.We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes SYN3 and NGLY1, which are involved in neurotransmitter release and proteasomal degradation, respectively.These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD 20892, USA. shrinerda@mail.nih.gov

ABSTRACT

Background: Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers.

Results: We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication.

Conclusions: We identified a single risk haplotype with a directionally consistent effect in both samples in the gene GAK, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes SYN3 and NGLY1, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.

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Genome-wide scans for single marker analysis. The red horizontal line indicates the significance level of 3.42 × 10-8.
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Figure 3: Genome-wide scans for single marker analysis. The red horizontal line indicates the significance level of 3.42 × 10-8.

Mentions: Under dominant coding, we identified no regions correlated with PD case/control status at a genome-wide significance level of 3.42 × 10-8 (Figure 3A). We identified seven independent loci at suggestive levels of association (Table 1). Of these, we replicated the region on chromosome 4p16 including the gene GAK. This region was discovered using unions of one, two, or three markers but was replicated only in the single marker analysis (Table 1). Using haplotype analysis, we found that the association in both samples was driven by the same low-frequency haplotype (TT) with an odds ratio of 1.58 (Table 2).


A unified framework for multi-locus association analysis of both common and rare variants.

Shriner D, Vaughan LK - BMC Genomics (2011)

Genome-wide scans for single marker analysis. The red horizontal line indicates the significance level of 3.42 × 10-8.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3040731&req=5

Figure 3: Genome-wide scans for single marker analysis. The red horizontal line indicates the significance level of 3.42 × 10-8.
Mentions: Under dominant coding, we identified no regions correlated with PD case/control status at a genome-wide significance level of 3.42 × 10-8 (Figure 3A). We identified seven independent loci at suggestive levels of association (Table 1). Of these, we replicated the region on chromosome 4p16 including the gene GAK. This region was discovered using unions of one, two, or three markers but was replicated only in the single marker analysis (Table 1). Using haplotype analysis, we found that the association in both samples was driven by the same low-frequency haplotype (TT) with an odds ratio of 1.58 (Table 2).

Bottom Line: We identified a single risk haplotype with a directionally consistent effect in both samples in the gene GAK, which is involved in clathrin-mediated membrane trafficking.We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes SYN3 and NGLY1, which are involved in neurotransmitter release and proteasomal degradation, respectively.These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD 20892, USA. shrinerda@mail.nih.gov

ABSTRACT

Background: Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers.

Results: We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication.

Conclusions: We identified a single risk haplotype with a directionally consistent effect in both samples in the gene GAK, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes SYN3 and NGLY1, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.

Show MeSH
Related in: MedlinePlus