Review of cancer among 4 religious sects: Evidence that life-styles are distinctive sets of risk factors

Alzheimer's Disease (AD) is a complex genetic disorder with four loci already identified. Mutations in three of these, the amyloid precursor protein, presenilin I, and presenilin II, cause early-onset AD. The apolipoprotein E (APOE) gene contributes primarily to late-onset AD. The APOE-4 allele acts in a dose-related fashion to increase risk and decrease the age-of-onset distribution in AD. We examined the effect of APOE on AD in a previously unstudied Amish population that has a lower prevalence of dementia compared with other populations. We sampled a large inbred family with 6 late-onset AD members. We also genotyped 53 individuals from the general Amish population as controls for the APOE allele frequency estimates. The frequency of the APOE-4 allele in the Amish controls was 0.037 +/- 0.02. This differed significantly compared with three independent sets of non-Amish white controls (p < 2 x 10(-4), p < 6 x 10(-5), and p < 2 x 10(-6)). In addition, all Amish AD-affected individuals had APOE 3/3 genotypes; no APOE X/4 or 4/4 individuals were observed. We suggest that the lower frequency of dementia in the Amish may be partially explained by the decreased frequency of the APOE-4 allele in this population, and that the inbred nature of this pedigree, with its strong clustering of cases contrasted against the lower frequency of dementia, indicates that additional genetic factors influence late-onset AD.

Alzheimer's disease and apolipoprotein E-4 allele in an Amish population

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.

A genome-wide linkage analysis of dementia in the Amish†

Populations of Old Order Amish, living in Pennsylvania, Ohio and Indiana, and isolated by their strict religious views, have provided human geneticists with a rich source of data.

Population studies and the Old Order Amish.

Genetic studies of 540 Paraguayan Indians from nine tribal groups and 51 Mennonites are presented for ABO, MNSs, P1, Rh, Kell, Lewis, Duffy, Diego; for serum immunoglobulins and haptoglobins, G6PD-deficiency, and thalassemia trait.



Group O gene frequencies for all Indian groups were 1.00; for r (cde), 0.00.



Tapiete, Lengua, Toba, and Sanapana Rz (CDE) frequencies were among the highest ever reported.



N frequencies were high for Ache Kwera (Guayaki), Lengua, Cheroti, Guarayu, Tapiete; N and s low for Ayore. MS frequencies were high for Sanapana, Lengua, Ayore; Ns for Tapiete. Diego was notably absent for Toba, Lengua, Guarayu, Tapiete, Ayore. Homogeneous frequencies for Fya (1.000) occurred among Guarayu and Tapiete, and for P1 among Guayaki. Inv(a) frequencies were low for Cheroti, Chulupi, Guayaki. Hp 1 among Guayaki (Ache Kwera 0.15) is lowest ever reported.



G6PD deficiency and abnormal hemoglobins were uniformly absent from all groups.



Mennonite results were homogeneous and point toward Dutch origins.



Differences among groups studied, and between Paraguayan and other Amerinds emphasize importance of genetic drift and founder principle. Abandonment of their tribes by mixed-blood offspring is partly responsible for apparent genetic purity and homogeneity of groups.

Genetic studies in Paraguay: blood group, red cell, and serum genetic patterns of the Guayaki and Ayore Indians, Mennonite settlers, and seven other Indian tribes of the Paraguayan Chaco.

W E Symon

Papers

Consanguinity and blood group distribution in an Amish Isolate.