OBJECTIVE: Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes. METHODS: We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics. RESULTS: We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD. CONCLUSIONS: We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.
OBJECTIVE: Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes. METHODS: We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics. RESULTS: We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD. CONCLUSIONS: We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.
Authors: Rosa M Canet-Avilés; Mark A Wilson; David W Miller; Rili Ahmad; Chris McLendon; Sourav Bandyopadhyay; Melisa J Baptista; Dagmar Ringe; Gregory A Petsko; Mark R Cookson Journal: Proc Natl Acad Sci U S A Date: 2004-06-04 Impact factor: 11.205
Authors: M H Polymeropoulos; C Lavedan; E Leroy; S E Ide; A Dehejia; A Dutra; B Pike; H Root; J Rubenstein; R Boyer; E S Stenroos; S Chandrasekharappa; A Athanassiadou; T Papapetropoulos; W G Johnson; A M Lazzarini; R C Duvoisin; G Di Iorio; L I Golbe; R L Nussbaum Journal: Science Date: 1997-06-27 Impact factor: 47.728
Authors: M C de Rijk; L J Launer; K Berger; M M Breteler; J F Dartigues; M Baldereschi; L Fratiglioni; A Lobo; J Martinez-Lage; C Trenkwalder; A Hofman Journal: Neurology Date: 2000 Impact factor: 9.910
Authors: Jessica C Greene; Alexander J Whitworth; Isabella Kuo; Laurie A Andrews; Mel B Feany; Leo J Pallanck Journal: Proc Natl Acad Sci U S A Date: 2003-03-17 Impact factor: 11.205
Authors: Vincenzo Bonifati; Patrizia Rizzu; Marijke J van Baren; Onno Schaap; Guido J Breedveld; Elmar Krieger; Marieke C J Dekker; Ferdinando Squitieri; Pablo Ibanez; Marijke Joosse; Jeroen W van Dongen; Nicola Vanacore; John C van Swieten; Alexis Brice; Giuseppe Meco; Cornelia M van Duijn; Ben A Oostra; Peter Heutink Journal: Science Date: 2002-11-21 Impact factor: 47.728
Authors: Enza Maria Valente; Patrick M Abou-Sleiman; Viviana Caputo; Miratul M K Muqit; Kirsten Harvey; Suzana Gispert; Zeeshan Ali; Domenico Del Turco; Anna Rita Bentivoglio; Daniel G Healy; Alberto Albanese; Robert Nussbaum; Rafael González-Maldonado; Thomas Deller; Sergio Salvi; Pietro Cortelli; William P Gilks; David S Latchman; Robert J Harvey; Bruno Dallapiccola; Georg Auburger; Nicholas W Wood Journal: Science Date: 2004-04-15 Impact factor: 47.728
Authors: Vikram Khurana; Jian Peng; Chee Yeun Chung; Pavan K Auluck; Saranna Fanning; Daniel F Tardiff; Theresa Bartels; Martina Koeva; Stephen W Eichhorn; Hadar Benyamini; Yali Lou; Andy Nutter-Upham; Valeriya Baru; Yelena Freyzon; Nurcan Tuncbag; Michael Costanzo; Bryan-Joseph San Luis; David C Schöndorf; M Inmaculada Barrasa; Sepehr Ehsani; Neville Sanjana; Quan Zhong; Thomas Gasser; David P Bartel; Marc Vidal; Michela Deleidi; Charles Boone; Ernest Fraenkel; Bonnie Berger; Susan Lindquist Journal: Cell Syst Date: 2017-01-25 Impact factor: 10.304
Authors: David N Cooper; Michael Krawczak; Constantin Polychronakos; Chris Tyler-Smith; Hildegard Kehrer-Sawatzki Journal: Hum Genet Date: 2013-07-03 Impact factor: 4.132
Authors: Janice L Farlow; Laurie A Robak; Kurt Hetrick; Kevin Bowling; Eric Boerwinkle; Zeynep H Coban-Akdemir; Tomasz Gambin; Richard A Gibbs; Shen Gu; Preti Jain; Joseph Jankovic; Shalini Jhangiani; Kaveeta Kaw; Dongbing Lai; Hai Lin; Hua Ling; Yunlong Liu; James R Lupski; Donna Muzny; Paula Porter; Elizabeth Pugh; Janson White; Kimberly Doheny; Richard M Myers; Joshua M Shulman; Tatiana Foroud Journal: JAMA Neurol Date: 2016-01 Impact factor: 18.302