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A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.

Abraham R, Moskvina V, Sims R, Hollingworth P, Morgan A, Georgieva L, Dowzell K, Cichon S, Hillmer AM, O'Donovan MC, Williams J, Owen MJ, Kirov G - BMC Med Genomics (2008)

Bottom Line: Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 x 10-7).We provide evidence for LRAT as a novel candidate gene for LOAD.LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Psychological Medicine, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK. AbrahamRA@Cardiff.ac.uk

ABSTRACT

Background: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case - control sample, reducing costs through the use of DNA pooling.

Methods: DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case - control sample used to construct the pools.

Results: Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach.For 109 SNPs outside the APOE locus, we obtained uncorrected p-values

Conclusion: We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.

No MeSH data available.


Related in: MedlinePlus

LD plot for SNPs in the region of LRAT. Linkage Disequilibrium plot (D' values shown) for tagSNPs chosen to cover an LD block containing LRAT. The most significant SNP from GWA study, rs727153, is in high LD with SNPs in LRAT.
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Figure 5: LD plot for SNPs in the region of LRAT. Linkage Disequilibrium plot (D' values shown) for tagSNPs chosen to cover an LD block containing LRAT. The most significant SNP from GWA study, rs727153, is in high LD with SNPs in LRAT.

Mentions: rs727153 is an intergenic SNP approximately 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). We genotyped additional SNPs in this region to test if our significant association extended into the LRAT gene. rs727153 is within an LD block flanked by SNPs rs11935519 and rs149225 (Chr4:156,005,695..156,040,821 – HapMap data Rel 21a/phaseII Jan07), which includes LRAT (Figure 5). Using a pair-wise approach in Haploview we identified 7 tagging SNPs required to cover the LD block, capturing all common SNPs with an r2 > 0.8 and individually genotyping them in our LOAD case – control sample. The results are presented in Table 2. Five SNPs are significantly associated with LOAD in this region, with a SNP in intron 2 of LRAT, rs201825 showing the strongest evidence (p-value = 1.7 × 10-6). After the addition of extra controls data from the 1958 birth cohort for the 4 SNPs in LRAT which have been genotyped in that sample, 3 became more significant (rs201825, p-value = 6.1 × 10-7) and the fourth remained unchanged.


A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.

Abraham R, Moskvina V, Sims R, Hollingworth P, Morgan A, Georgieva L, Dowzell K, Cichon S, Hillmer AM, O'Donovan MC, Williams J, Owen MJ, Kirov G - BMC Med Genomics (2008)

LD plot for SNPs in the region of LRAT. Linkage Disequilibrium plot (D' values shown) for tagSNPs chosen to cover an LD block containing LRAT. The most significant SNP from GWA study, rs727153, is in high LD with SNPs in LRAT.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570675&req=5

Figure 5: LD plot for SNPs in the region of LRAT. Linkage Disequilibrium plot (D' values shown) for tagSNPs chosen to cover an LD block containing LRAT. The most significant SNP from GWA study, rs727153, is in high LD with SNPs in LRAT.
Mentions: rs727153 is an intergenic SNP approximately 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). We genotyped additional SNPs in this region to test if our significant association extended into the LRAT gene. rs727153 is within an LD block flanked by SNPs rs11935519 and rs149225 (Chr4:156,005,695..156,040,821 – HapMap data Rel 21a/phaseII Jan07), which includes LRAT (Figure 5). Using a pair-wise approach in Haploview we identified 7 tagging SNPs required to cover the LD block, capturing all common SNPs with an r2 > 0.8 and individually genotyping them in our LOAD case – control sample. The results are presented in Table 2. Five SNPs are significantly associated with LOAD in this region, with a SNP in intron 2 of LRAT, rs201825 showing the strongest evidence (p-value = 1.7 × 10-6). After the addition of extra controls data from the 1958 birth cohort for the 4 SNPs in LRAT which have been genotyped in that sample, 3 became more significant (rs201825, p-value = 6.1 × 10-7) and the fourth remained unchanged.

Bottom Line: Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 x 10-7).We provide evidence for LRAT as a novel candidate gene for LOAD.LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Psychological Medicine, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK. AbrahamRA@Cardiff.ac.uk

ABSTRACT

Background: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case - control sample, reducing costs through the use of DNA pooling.

Methods: DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case - control sample used to construct the pools.

Results: Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach.For 109 SNPs outside the APOE locus, we obtained uncorrected p-values

Conclusion: We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.

No MeSH data available.


Related in: MedlinePlus