Objective: Our objective is to undertake the most extensive screening of the impact of homozygosity in Parkinson’s disease (PD) etiology across diverse populations. We aim to investigate to what extent recessive allelic architecture might define a portion of PD heritability by investigating excess of homozygosity in cases relative to controls in a global context. Here we estimated the degree of inbreeding across diverse populations, and we prioritised regions with potential recessive inheritance where rare variants may be influencing the genetic architecture of disease.

Background: Long regions of consecutive homozygous genotypes, known as runs of homozygosity (ROHs), result from inbreeding and recessive inheritance (1,2). Despite arising from common ancestors, ROHs are found in outbred populations, with potential links to complex phenotypes through recessive patterns of inheritance.

Method: We explored ROHs leveraging genotyping imputed data from the sixth release of the Global Parkinson’s Genetics Program (GP2) across nine ancestral populations, comprising 16,599 PD cases and 13,585 healthy controls. Whole-genome sequencing (WGS) data from GP2 release 6 included 1,956 individuals, comprising 1,647 PD cases and 309 healthy controls. The parameters investigated included the total length of ROHs, the count of ROHs, the average length of ROHs, and inbreeding coefficient estimates. Additionally, we intersected ROHs within PD recessive known genes as well as PD genes within known risk loci and assess differences in cases versus controls.

Results: Here, we provide a research framework to look for ROHs in PD in a large scale and unbiased manner. Our results showed that PD cases harbour enriched homozygosity, suggesting that unknown and novel recessive effects may explain a proportion of PD missing heritability.

Conclusion: The identification of autosomal recessive genes for PD to date has been mostly based on the identification of specific consanguineous families in European populations. Yet, the genetic architecture of disease differs across populations. The present work expands our current knowledge of the genetic aetiology of PD in a global context. Moreover, a comprehensive expansion of homozygosity analysis to include WGS data promises to provide a more profound insight into the intricate genetics of PD.

References: 1.    Szpiech ZA, Xu J, Pemberton TJ, Peng W, Zöllner S, Rosenberg NA, et al. Long runs of homozygosity are enriched for deleterious variation. Am J Hum Genet. 2013 Jul 11;93(1):90–102.
2.    Moreno-Grau S, Fernández MV, de Rojas I, Garcia-González P, Hernández I, Farias F, et al. Long runs of homozygosity are associated with Alzheimer’s disease. Transl Psychiatry. 2021 Feb 24;11(1):142.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-assessment-of-homozygosity-in-parkinsons-disease-across-diverse-ancestral-population/