A genome‐wide linkage analysis of dementia in the Amish

Abstract

Susceptibility genes for Alzheimer's disease are proving to be highly challenging to detect and verify. Population heterogeneity may be a significant confounding factor contributing to this difficulty. To increase the power for disease susceptibility gene detection, we conducted a genome-wide genetic linkage screen using individuals from the relatively isolated, genetically homogeneous, Amish population. Our genome linkage analysis used a 407-microsatellite-marker map (average density 7 cM) to search for autosomal genes linked to dementia in five Amish families from four Midwestern U.S. counties. Our highest two-point lod score (3.01) was observed at marker D4S1548 on chromosome 4q31. Five other regions (10q22, 3q28, 11p13, 4q28, 19p13) also demonstrated suggestive linkage with markers having two-point lod scores >2.0. While two of these regions are novel (4q31 and 11p13), the other regions lie close to regions identified in previous genome scans in other populations. Our results identify regions of the genome that may harbor genes involved in a subset of dementia patients, in particular the North American Amish community.

Genetics of Alzheimer's Disease: A Centennial Review

“…Two novel loci were detected at chromosomes 2q34 in early onset AD (50-60 years) and 15q22 in very late onset AD (≥79 years), in addition to increasing the previously detected linkage signal at 9p from 3.0 to 4.6 (n=334 families, 60-75 years). The chromosome 2q34 locus also showed evidence of linkage in Caribbean Hispanics [ 132 ], along with two other regions encompassing 2q34 detected in Amish families [ 135 ]. The 15q region is at least 17 cM away from the nearest risk region identified in another study [ 123 ].…”

“…A summary of the key characteristics of these studies are presented in Table 2. As seen here, there are essentially three groups of studies: "A" denotes those whole genome linkage studies on AD families or sibpairs [ 117,121,126,127,129,132,135,136 ]. These studies are independent in that they were either performed entirely on ethnically distinct datasets of Caribbean Hispanic [ 126,132 ] [ 121 ] based on the similar sources of the study subjects, although the extent of overlap is not explicitly mentioned in their latter publication.…”

“…The autopsy confirmed subset also had another downstream region on chromosome 9q with evidence of linkage. In the substantially overlapping dataset analyzed by Myers et 3) Alternative analytical methods to detect risk loci for LOAD-In addition to the 9 whole genome linkage or association analyses in predominantly non-overlapping samples [ 117,119,121,123,126,127,129,130,132,135,136 ], seven linkage studies are presented here, which utilized alternative analytical strategies to re-assess the data in overlapping datasets [ 122,124,125,128,131,133,134 ]. We will briefly discuss their approaches and results, as they bring potential new understanding and evidence to the LOAD risk loci.…”

Linkage and association of successful aging to the 6q25 region in large Amish kindreds

“…All individuals had to be cognitively intact (education-adjusted modified mini-mental state examination (3MS) >86). If someone had an education-adjusted 3MS <87 but was determined not to be cognitively impaired after further neuropsychological testing and evaluation at a consensus conference (Hahs et al 2006), they would be classified as SA if they met the other criteria. SA individuals did not have significant depressive symptoms (geriatric depression scale (GDS) score <6).…”

Genetic analysis of the RELN gene: Gender specific association with Alzheimer’s disease

“…RELN gene maps to 7q22, which is located next to an AD linkage region on the long arm of chromosome 7 (Pericak-Vance et al, 2000;Hahs et al, 2006;Ertekin-Taner, 2007). Reelin plays a crucial role in the migration and positioning of neurons during brain development and has been linked to processes of synaptic plasticity, learning and memory formation (Herz and Chen, 2006;Lakatosova and Ostatnikova, 2012).…”