Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Abstract

The aim of the study was to identify chromosomal regions containing putative genetic variants influencing age-at-onset in familial late-onset Alzheimer's disease. Data from a genome-wide scan that included genotyping of APOE was analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age-at-onset of 73.3 years multiply affected by late-onset Alzheimer's disease. Two-point and multipoint analyses were conducted using variance component methods from 376 microsatellite markers with an average inter-marker distance of 9.3 cM. Family-based test of association were also conducted for the same set of markers. Age-at-onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ε4 lowered the age-at-onset by three years. Using linkage analysis strategy, the highest LOD scores were obtained using a conservative definition of LOAD at 5q15 (LOD 3.1) 17q25.1 (LOD=2.94) and 14q32.12 (LOD=2.36) and 7q36.3 (LOD=2.29) in covariate adjusted models that included APOE-ε4. Both linkage and family-based association identified 17p13 as a candidate region. In addition, family-based association analysis showed markers at 12q13 (p=0.00002), 13q (p=0.00043) and 14q23 (p=0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age-at-onset of late onset

Genome‐wide linkage analyses of non‐Hispanic white families identify novel loci for familial late‐onset Alzheimer's disease

“…This locus is a considerable distance (~33 cM) from the PSEN1 locus at 14q24. Suggestive linkage (Two-point LOD = 2.60) has been reported at 14q32 in an age-at-onset linkage analysis in Hispanic LOAD families [28]. The 1-LOD limit identified a region 0.78 Mbp in length containing C14orf177 and Mir_320, both of which have some support for involvement in dementia-related disease and processes.…”

Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes

“…The Collaborative Aging and Memory Project (CAMP) subjects are from the Amish communities of central Ohio and northern Indiana9–10. The Columbia University (CU) subjects are a Hispanic cohort described in detail elsewhere11. The Framingham Heart Study (FHS) is a single-site, community-based, ongoing cohort study described elsewhere12–14.…”

Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease

“…14 Subsequent genome-wide linkage scans examining AAO in AD patients and unaffected family members (using age at study entry) found suggestive evidence of linkage on chromosome 19 to APOE (LOD = 3.28), 15 which was confirmed in later studies. 16 Multiple studies identified other suggestive linkage signals on chromosomes 4q, 8q, 16 1q, 6p, 17 7q, 15, and 19p 18 in Caucasian families, and chromosomes 5q, 7q, 14q, and 17q 19 in Caribbean Hispanics, though the specific loci driving these linkage signals remain unknown. More recently, an AAO GWAS in 2,222 Caucasian AD cases confirmed association at APOE , and also found strong evidence of association ( P =4.95×10 −7 ) on chromosome 4q31.3 in the gene DCHS2 .…”