TY - JOUR
T1 - Genome-Wide Assessment Reveals Ancestral Differences in Homozygosity Patterns Potentially Linked to Parkinson's Disease Etiology
AU - Step, Kathryn
AU - Hernández, Carlos F.
AU - Khani, Marzieh
AU - Eltaraifee, Esraa
AU - Hernández-Medrano, Ana Jimena
AU - Kung, Pin Jui
AU - Ostrožovičová, Miriam
AU - Zirra, Alexandra
AU - Pérez-Palma, Eduardo
AU - Mencacci, Niccolò E.
AU - Keller Sarmiento, Ignacio J.
AU - Morris, Huw R.
AU - Mata, Ignacio F.
AU - Acosta-Uribe, Juliana
AU - Fang, Zih Hua
AU - Bandres-Ciga, Sara
AU - Mecheri, Yasser
AU - Sofiane, Bouchetara Mohamed
AU - Traki, Benhassine
AU - Gatto, Emilia Mabel
AU - Kauffman, Marcelo
AU - Capparelli, Federico
AU - Muller, Maria Valentina
AU - Tela, Marcela Susana
AU - Adamec, Dario Sergio
AU - Avila, Cesar
AU - Khachatryan, Samson
AU - Tavadyan, Zaruhi
AU - Isayan, Mariam
AU - Shepherd, Claire
AU - Kumar, Kishore
AU - Ellis, Melina
AU - Rentería, Miguel
AU - Koks, Sulev
AU - Rowel, Simon
AU - Yeow, Dennis
AU - Sue, Carolyn
AU - Ocampo, Victor
AU - Wools, Christine
AU - Weiss, Keren Aliza
AU - Siow, Sue Faye
AU - Davis, Ryan
AU - Willis, Amanda
AU - He, Steven
AU - Wilcox, Robert Arthur
AU - Howting, Denise
AU - Price, Jack David
AU - Cheong, Pak Leng
AU - Tchan, Michel
AU - Krüger, Rejko
AU - the Global Parkinson's Genetics Program (GP2)
N1 - © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
PY - 2026/5
Y1 - 2026/5
N2 - BACKGROUND: Recessive genetic variation and extended runs of homozygosity (ROHs) may contribute to the unexplained heritability of Parkinson's disease (PD), particularly in diverse and understudied populations.OBJECTIVE: We conducted the first large-scale, multi-ancestral investigation of PD to examine the impact of genome-wide homozygosity on disease risk and age at onset (AAO). Using genotyping, imputed, and whole-genome sequencing data from 36,127 PD cases and 19,475 controls across nine ancestral populations from the Global Parkinson's Genetics Program, we aimed to identify novel regions of homozygosity contributing to PD heritability.METHODS: We analyzed ROHs for total length (SROH), number (NROH), average length (AVROH), and genomic inbreeding coefficient (FROH). ROHs were intersected with known PD, pallido-pyramidal syndrome, and atypical parkinsonism gene regions and risk loci to assess pleomorphic or pleiotropic contributions. Homozygosity mapping identified ROH overlaps in families, consanguineous individuals, and early-onset PD (EOPD) cases.RESULTS: Significant differences in SROH, AVROH, NROH, and FROH were observed between case status across ancestries, persisting after excluding known PD-associated recessive genes. Our analysis revealed distinct patterns of ROH enrichment associated with AAO, suggesting recessive genetic modifiers of PD. Homozygosity mapping was used to prioritize 52 variants either segregating in families or present in individuals with consanguinity. In total, 1,559 ROHs in consanguineous individuals and EOPD overlapped known PD gene regions and risk loci.CONCLUSIONS: ROH regions contribute to PD heritability across ancestries, partly reflecting recessive genetic architecture. Larger and more diverse whole-genome sequencing studies are needed to identify rare recessive variants influencing PD risk. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
AB - BACKGROUND: Recessive genetic variation and extended runs of homozygosity (ROHs) may contribute to the unexplained heritability of Parkinson's disease (PD), particularly in diverse and understudied populations.OBJECTIVE: We conducted the first large-scale, multi-ancestral investigation of PD to examine the impact of genome-wide homozygosity on disease risk and age at onset (AAO). Using genotyping, imputed, and whole-genome sequencing data from 36,127 PD cases and 19,475 controls across nine ancestral populations from the Global Parkinson's Genetics Program, we aimed to identify novel regions of homozygosity contributing to PD heritability.METHODS: We analyzed ROHs for total length (SROH), number (NROH), average length (AVROH), and genomic inbreeding coefficient (FROH). ROHs were intersected with known PD, pallido-pyramidal syndrome, and atypical parkinsonism gene regions and risk loci to assess pleomorphic or pleiotropic contributions. Homozygosity mapping identified ROH overlaps in families, consanguineous individuals, and early-onset PD (EOPD) cases.RESULTS: Significant differences in SROH, AVROH, NROH, and FROH were observed between case status across ancestries, persisting after excluding known PD-associated recessive genes. Our analysis revealed distinct patterns of ROH enrichment associated with AAO, suggesting recessive genetic modifiers of PD. Homozygosity mapping was used to prioritize 52 variants either segregating in families or present in individuals with consanguinity. In total, 1,559 ROHs in consanguineous individuals and EOPD overlapped known PD gene regions and risk loci.CONCLUSIONS: ROH regions contribute to PD heritability across ancestries, partly reflecting recessive genetic architecture. Larger and more diverse whole-genome sequencing studies are needed to identify rare recessive variants influencing PD risk. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
KW - genome-wide homozygosity
KW - global Parkinson's Genetics Program (GP2)
KW - multi-ancestral analysis
KW - parkinson's disease
KW - runs of homozygosity
KW - Genome-Wide Association Study
KW - Humans
KW - Middle Aged
KW - Male
KW - Genetic Predisposition to Disease/genetics
KW - Parkinson Disease/genetics
KW - Homozygote
KW - Age of Onset
KW - Female
KW - Aged
UR - https://www.scopus.com/pages/publications/105033958871
UR - https://pubmed.ncbi.nlm.nih.gov/41808632/
U2 - 10.1002/mds.70182
DO - 10.1002/mds.70182
M3 - Article
C2 - 41808632
AN - SCOPUS:105033958871
SN - 0885-3185
VL - 41
SP - 1128
EP - 1140
JO - Movement Disorders
JF - Movement Disorders
IS - 5
ER -