Objective: Here, we investigated the contribution of DAGLB variants to PD across diverse ancestries using large-scale data from the Global Parkinson’s Genetics Program (GP2).

Background: Biallelic DAGLB variants have been reported in dopa-responsive autosomal recessive early-onset Parkinson’s disease (EOPD) in a small number of cases from East Asian and North African populations.

Method: We analyzed GP2 Release 11 data, including genotyping, whole-genome sequencing (WGS), and clinical exome sequencing (CES) across eleven ancestry groups. Variants were annotated using ANNOVAR and prioritized using in silico pathogenicity prediction tools. Associations between common DAGLB variants (MAF≥1%) and PD risk were assessed using generalized linear models, and gene-based burden analysis were performed for rare variants.

Results: We identified four unresolved EOPD cases carrying rare DAGLB variants in homozygous or putative biallelic states. Three individuals were male with age at onset between 39 and 41 years and no reported family history of PD; one was female with unavailable clinical details. The identified variants included one homozygous stop-gain (p.Lys406*), two homozygous missense variants (p.Ile76Asn and p.Pro107Leu), and one individual carrying two rare heterozygous variants (p.Asp234Asn and p.Leu644Arg; phase unknown). Two unaffected male controls also carried rare DAGLB variants: one homozygous (p.Ala618Thr) and two heterozygous variants (p.Val192Met and p.Gly445Arg). None of the previously reported DAGLB variants were observed in biallelic form in our cohort. Single-variant association analysis identified DAGLB p.Leu456Val significantly associated with PD risk in individuals of European ancestry in WGS (Bonf p-value=0.037) but not in genotyping data. Gene-based burden analysis showed a significant association between rare variants (MAF<1%) and PD risk in East Asian ancestry in genotyping data (p-value=0.008), with no significant associations observed across other ancestries or variant classes.

Conclusion: Our findings expand the ancestral diversity of individuals carrying potentially pathogenic DAGLB variants and provide no evidence for a major contribution of common DAGLB variants to PD risk.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-daglb-variants-with-early-onset-parkinsons-disease-across-populations/