Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 78, Issue 1, Pages 78-88Publisher
CELL PRESS
DOI: 10.1086/498851
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Funding
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [T32HG000045] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM065509] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [U01MH046373, U01MH046281, U01MH046290, P50MH060451] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS039764] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P50AG016570, P50AG008671, U24AG021886, P50AG005131, P50AG005681, P50AG005128, P50AG005146, Z01AG000950, P01AG003991, R01AG016208] Funding Source: NIH RePORTER
- Intramural NIH HHS Funding Source: Medline
- Medical Research Council [G0300429, G0701075, G9810900] Funding Source: Medline
- NHGRI NIH HHS [T32 HG000045] Funding Source: Medline
- NIA NIH HHS [P50 AG008671, P01 AG03991, P50-AG08671, AG05128, AG 05146, P50 AG005146, R01 AG16208, P50 AG016570, P50 AG005128, P50 AG16570, P50 AG05681, P50 AG005681, U24 AG021886, P50 AG005131, R01 AG016208, P50 AG05131, P01 AG003991] Funding Source: Medline
- NIGMS NIH HHS [P50 GM065509, GM065509] Funding Source: Medline
- NIMH NIH HHS [U01 MH046281, MH60451, U01 MH046373, U01 MH046290, P50 MH060451] Funding Source: Medline
- NINDS NIH HHS [NS39764, P50 NS039764] Funding Source: Medline
- MRC [G0300429, G9810900] Funding Source: UKRI
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Strong evidence of linkage to late-onset Alzheimer disease ( LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 genebased single-nucleotide polymorphisms ( SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A ( LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants ( e. g., noncoding RNAs) in the pathogenesis of this disorder.
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