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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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Comparison of single marker and multi-locus methods. A) The observed joint genotype counts for rs1564282 and rs2061846. One control with the CT genotype at rs1564282 had a missing genotype at rs2061846. B) Single marker analysis for rs1564282 under additive coding. C) Single marker analysis for rs2061846 under additive coding. D) Single marker analysis of rs1564282 under dominant coding. E) Single marker analysis of rs2061846 under dominant coding. "-" indicates either allele. F) Haplotype analysis. G) Union analysis under dominant coding.
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Figure 4: Comparison of single marker and multi-locus methods. A) The observed joint genotype counts for rs1564282 and rs2061846. One control with the CT genotype at rs1564282 had a missing genotype at rs2061846. B) Single marker analysis for rs1564282 under additive coding. C) Single marker analysis for rs2061846 under additive coding. D) Single marker analysis of rs1564282 under dominant coding. E) Single marker analysis of rs2061846 under dominant coding. "-" indicates either allele. F) Haplotype analysis. G) Union analysis under dominant coding.

Mentions: To directly compare single marker analysis, haplotype analysis, and our multi-locus method, we examined the first multi-locus union in Table 1, which consisted of SNPs rs1564282 and rs2061846, using the replication sample (Figure 4A). By 2 × 3 contingency table analysis of genotypes, rs1564282 was significantly associated with PD (Figure 4B) but rs2061846 was not (Figure 4C). Similarly, by 2 × 2 contingency table analysis under dominant coding, rs1564282 was significantly associated with PD (Figure 4D) but rs2061846 was not (Figure 4E). Haplotype analysis revealed significant association with PD for the haplotype consisting of the minor allele at rs1564282 and the major allele at rs2061846, i.e., haplotype TT vs. haplotypes CC and CT with haplotype TC being unobserved (Figure 4F). Under dominant coding, 2 × 2 contingency table analysis of the union did not yield significant association, because the union tested multi-locus genotype CCTT vs. the other eight genotypes, effectively attenuating the signal of haplotype TT (Figure 4G).


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

Shriner D, Vaughan LK - BMC Genomics (2011)

Comparison of single marker and multi-locus methods. A) The observed joint genotype counts for rs1564282 and rs2061846. One control with the CT genotype at rs1564282 had a missing genotype at rs2061846. B) Single marker analysis for rs1564282 under additive coding. C) Single marker analysis for rs2061846 under additive coding. D) Single marker analysis of rs1564282 under dominant coding. E) Single marker analysis of rs2061846 under dominant coding. "-" indicates either allele. F) Haplotype analysis. G) Union analysis under dominant coding.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Comparison of single marker and multi-locus methods. A) The observed joint genotype counts for rs1564282 and rs2061846. One control with the CT genotype at rs1564282 had a missing genotype at rs2061846. B) Single marker analysis for rs1564282 under additive coding. C) Single marker analysis for rs2061846 under additive coding. D) Single marker analysis of rs1564282 under dominant coding. E) Single marker analysis of rs2061846 under dominant coding. "-" indicates either allele. F) Haplotype analysis. G) Union analysis under dominant coding.
Mentions: To directly compare single marker analysis, haplotype analysis, and our multi-locus method, we examined the first multi-locus union in Table 1, which consisted of SNPs rs1564282 and rs2061846, using the replication sample (Figure 4A). By 2 × 3 contingency table analysis of genotypes, rs1564282 was significantly associated with PD (Figure 4B) but rs2061846 was not (Figure 4C). Similarly, by 2 × 2 contingency table analysis under dominant coding, rs1564282 was significantly associated with PD (Figure 4D) but rs2061846 was not (Figure 4E). Haplotype analysis revealed significant association with PD for the haplotype consisting of the minor allele at rs1564282 and the major allele at rs2061846, i.e., haplotype TT vs. haplotypes CC and CT with haplotype TC being unobserved (Figure 4F). Under dominant coding, 2 × 2 contingency table analysis of the union did not yield significant association, because the union tested multi-locus genotype CCTT vs. the other eight genotypes, effectively attenuating the signal of haplotype TT (Figure 4G).

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