Dissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population.

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. The apolipoprotein E (ApoE) ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic white populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in ε4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to ~80 of Amerindian (AI) ancestry provides a unique opportunity to assess the role of AI ancestry in AD. In this study, we assess the effect of the ApoE ε4 allele on AD in the Peruvian population. A total of 79 AD cases and 128 unrelated cognitive healthy controls from Peruvian population were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array v2.0. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE ε4 allele on AD was tested using a logistic regression model by adjusting for age, gender, and population substructure (first 3 principal components). Results showed that the genetic ancestry surrounding the ApoE gene is predominantly AI (60.6%) and the ε4 allele is significantly associated with increased risk of AD in the Peruvian population (odds ratio = 5.02, confidence interval: 2.3-12.5, p-value = 2e-4). Our results showed that the risk for AD from ApoE ε4 in Peruvians is higher than we have observed in non-Hispanic white populations. Given the high admixture of AI ancestry in the Peruvian population, it suggests that the AI genetic ancestry local to the ApoE gene is contributing to a strong risk for AD in ε4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE ε4 and the ancestral backgrounds located around the genomic region of ApoE gene.

The Puerto Rico Alzheimer Disease Initiative (PRADI): A Multisource Ascertainment Approach.

INTRODUCTION: Puerto Ricans, the second largest Latino group in the continental US, are underrepresented in genomic studies of Alzheimer disease (AD). To increase representation of this group in genomic studies of AD, we developed a multisource ascertainment approach to enroll AD patients, and their family members living in Puerto Rico (PR) as part of the Alzheimer's Disease Sequencing Project (ADSP), an international effort to advance broader personalized/precision medicine initiatives for AD across all populations. METHODS: The Puerto Rico Alzheimer Disease Initiative (PRADI) multisource ascertainment approach was developed to recruit and enroll Puerto Rican adults aged 50 years and older for a genetic research study of AD, including individuals with cognitive decline (AD, mild cognitive impairment), their similarly, aged family members, and cognitively healthy unrelated individuals age 50 and up. Emphasizing identification and relationship building with key stakeholders, we conducted ascertainment across the island. In addition to reporting on PRADI ascertainment, we detail admixture analysis for our cohort by region, group differences in age of onset, cognitive level by region, and ascertainment source. RESULTS: We report on 674 individuals who met standard eligibility criteria [282 AD-affected participants (42% of the sample), 115 individuals with mild cognitive impairment (MCI) (17% of the sample), and 277 cognitively healthy individuals (41% of the sample)]. There are 43 possible multiplex families (10 families with 4 or more AD-affected members and 3 families with 3 AD-affected members). Most individuals in our cohort were ascertained from the Metro, Bayamón, and Caguas health regions. Across health regions, we found differences in ancestral backgrounds, and select clinical traits. DISCUSSION: The multisource ascertainment approach used in the PRADI study highlights the importance of enlisting a broad range of community resources and providers. Preliminary results provide important information about our cohort that will be useful as we move forward with ascertainment. We expect that results from the PRADI study will lead to a better understanding of genetic risk for AD among this population.

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations.

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.

Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease.

INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.

myotilin Mutation found in second pedigree with LGMD1A.

Limb-girdle muscular dystrophy 1A (LGMD1A [MIM 159000]) is an autosomal dominant form of muscular dystrophy characterized by adult onset of proximal weakness progressing to distal muscle weakness. We have reported elsewhere a mutation in the myotilin gene in a large, North American family of German descent. Here, we report the mutation screening of an additional 86 families with a variety of neuromuscular pathologies. We have identified a new myotilin mutation in an Argentinian pedigree with LGMD1 that is predicted to result in the conversion of serine 55 to phenylalanine (S55F). This mutation has not been found in 392 control chromosomes and is located in the unique N-terminal domain of myotilin, only two residues from the T57I mutation reported elsewhere. Both T57I and S55F are located outside the alpha-actinin and gamma-filamin binding sites within myotilin. The identification of two independent pedigrees with the same disease, each bearing a different mutation in the same gene, has long been the gold standard for establishing a causal relationship between defects in a gene and the resultant disease. As a description of the second known pedigree with LGMD1A, this finding constitutes that gold standard of proof that mutations in the myotilin gene cause LGMD1A.