title: The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.
abstract: BACKGROUND
  We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.
  
  
  METHODS
  A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.
  
  
  RESULTS
  Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.
  
  
  CONCLUSIONS
  Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA. jlatoure@bu.edu
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lew
authors.forename: Oksana
authors.initials: O
authors.lastname: Suchowersky
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Golbe
authors.forename: Margery H
authors.initials: MH
authors.lastname: Mark
authors.forename: John H
authors.initials: JH
authors.lastname: Growdon
authors.forename: G Frederick
authors.initials: GF
authors.lastname: Wooten
authors.forename: Ray L
authors.initials: RL
authors.lastname: Watts
authors.forename: Mark
authors.initials: M
authors.lastname: Guttman
authors.forename: Brad A
authors.initials: BA
authors.lastname: Racette
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.forename: Anwar
authors.initials: A
authors.lastname: Ahmed
authors.forename: Holly A
authors.initials: HA
authors.lastname: Shill
authors.forename: Carlos
authors.initials: C
authors.lastname: Singer
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.forename: Michela
authors.initials: M
authors.lastname: Zini
authors.forename: Marie H
authors.initials: MH
authors.lastname: Saint-Hilaire
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Hendricks
authors.forename: Sally
authors.initials: S
authors.lastname: Williamson
authors.forename: Michael W
authors.initials: MW
authors.lastname: Nagle
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.forename: Tiffany
authors.initials: T
authors.lastname: Massood
authors.forename: Karen W
authors.initials: KW
authors.lastname: Huskey
authors.forename: Jason M
authors.initials: JM
authors.lastname: Laramie
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Baker
authors.forename: Ilia
authors.initials: I
authors.lastname: Itin
authors.forename: Irene
authors.initials: I
authors.lastname: Litvan
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Alastair
authors.initials: A
authors.lastname: Corbett
authors.forename: Martha
authors.initials: M
authors.lastname: Nance
authors.forename: Edward
authors.initials: E
authors.lastname: Drasby
authors.forename: Stuart
authors.initials: S
authors.lastname: Isaacson
authors.forename: David J
authors.initials: DJ
authors.lastname: Burn
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Jomana
authors.initials: J
authors.lastname: Al-hinti
authors.forename: Anette T
authors.initials: AT
authors.lastname: Moller
authors.forename: Karen
authors.initials: K
authors.lastname: Ostergaard
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Sherman
authors.forename: Richard
authors.initials: R
authors.lastname: Roxburgh
authors.forename: Barry
authors.initials: B
authors.lastname: Snow
authors.forename: John T
authors.initials: JT
authors.lastname: Slevin
authors.forename: Franca
authors.initials: F
authors.lastname: Cambi
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005998:Glycine / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D019683:Penetrance; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011897:Random Allocation; D012694:Serine / Q000235:genetics*; D012737:Sex Factors
chemical_list: D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005998:Glycine