[R21] Leveraging Consanguinity to Uncover the Genomic Architecture of Alzheimer's Disease
Ente: National Institute on Aging
Scadenza: 2027-06-30
Importo max: 163.304 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Currently, 57 million people live with dementia worldwide, and this number is set to reach 139 million by 2050.1 Alzheimer’s Disease (AD) is the most common form of dementia, accounting for 50-75% of all cases. Familial aggregation of genetic predisposition is a major risk factor for AD.3 AD cases have enriched homozygosity, hallmarked by long Runs of Homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.4 The current knowledge of AD is based on data derived from high-income white Caucasians from Western countries. Few cohorts represent South Asian populations (e.g., UK Biobank5) and even fewer investigate genetic and phenotypic architecture in AD progression. UK Gene & Health Study (G&HS) recently reported on dose-dependent APOE 𝜺𝜺4 variation for dementia risk in British Pakistanis and Bangladeshis, a population with high consanguinity.6
Consanguinity is a powerful founder event that leads to reduced genetic variation and increased risk for recessive diseases (RD).7 Close to 1.1 billion people live in cultures where it is customary to have consanguineous marriage (20-50% of all marriages)8-10 and one in every three marriages is between first or second cousins.9 First cousins share 1/8th of their genes inherited from their grandparents, so their progeny is autozygous at 1 of 16 of all loci.11,12 The term autozygosity refers to homozygosity of alleles that are identical by descent (inherited from a common ancestor). The prevalence of congenital anomalies due to autosomal RD in the offspring of first cousin marriages is about 1.7–2.8% higher than the general population risk.13-15 High susceptibility genes play a key role in the expression of several etiologically heterogeneous diseases, including AD.16-22 If such genes are transmitted in an autosomal recessive manner, then consanguinity could be a determining factor,14,23 e.g., AD in an Israeli Arab community,24 schizophrenia in southern Israel,17 and stroke in an isolated community in the Netherlands.25 Rare and novel autosomal RD exist in consanguineous communities,26,27 such as in Pakistan where consanguinity is highly prevalent (63%), followed by Saudi Arabia (50%), Afghanistan (40%), and Iran (30%).9
A standard Genome Wide Sequencing Analysis (GWAS) searches for known genes involved in Mendelian diseases. Exome sequencing of 75000 Pakistanis recently identified a NOTCH3 genetic missense variant (30x enriched among South Asians), underscoring the need for genetic variety.28 The Longitudinal Aging Study in India - Diagnostic Assessment of Dementia (LASI-DAD) study reported 24 million single nucleotide variants (SNVs) in 2,762 South Indians, absent in existing databases,7 higher homozygosity, and increased risk of RD. The UK-based G&HS found a causal variant within the PIEZO1 locus leading to alterations in red cell traits in 51,104 British South Asians, only common in these ancestries.29 The recent APOE 𝜺𝜺4 finding in British South
Istituzione: PALO ALTO VETERANS INSTIT FOR RESEARCH
PI: MAHEEN MAUSOOF ADAMSON
Progetto: 5R21AG085568-02
Settori: National Institute on Aging
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