LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago.
The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic determinant of Parkinson disease (PD) identified to date. It accounts for 1%-7% of PD in patients of European origin and 20%-40% in Ashkenazi Jews and North African Arabs with PD. Previous studies concluded that patients from these populations all shared a common Middle Eastern founder who lived in the 13th century. We tested this hypothesis by genotyping 25 microsatellite and single-nucleotide-polymorphism markers in 22 families with G2019S and observed two distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in three European American families. Using a maximum-likelihood method, we estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Our data suggest two separate founding events for G2019S in these populations, beginning at a time that coincides with the Jewish Diasporas.
Zabetian
Cyrus P
CP
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. zabetian@u.washington.edu
Hutter
Carolyn M
CM
Yearout
Dora
D
Lopez
Alexis N
AN
Factor
Stewart A
SA
Griffith
Alida
A
Leis
Berta C
BC
Bird
Thomas D
TD
Nutt
John G
JG
Higgins
Donald S
DS
Roberts
John W
JW
Kay
Denise M
DM
Edwards
Karen L
KL
Samii
Ali
A
Payami
Haydeh
H
D000352:Africa, Northern; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D005190:Family; D005260:Female; D006239:Haplotypes; D006801:Humans; D007585:Jews / Q000235:genetics*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008877:Middle East; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012984:Software; D044465:White People / Q000235:genetics*
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases