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- PMID: 23588557
- UKPMCID: 23588557
- DOI: 10.1001/jamaneurol.2013.1925
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A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies.
Nalls, Michael A; Duran, Raquel; Lopez, Grisel; Kurzawa-Akanbi, Marzena; McKeith, Ian G; Chinnery, Patrick F; Morris, Christopher M; Theuns, Jessie; Crosiers, David; Cras, Patrick; Engelborghs, Sebastiaan; De Deyn, Peter Paul; Van Broeckhoven, Christine; Mann, David M A; Snowden, Julie; Pickering-Brown, Stuart; Halliwell, Nicola; Davidson, Yvonne; Gibbons, Linda; Harris, Jenny; Sheerin, Una-Marie; Bras, Jose; Hardy, John; Clark, Lorraine; Marder, Karen; Honig, Lawrence S; Berg, Daniela; Maetzler, Walter; Brockmann, Kathrin; Gasser, Thomas; Novellino, Fabiana; Quattrone, Aldo; Annesi, Grazia; De Marco, Elvira Valeria; Rogaeva, Ekaterina; Masellis, Mario; Black, Sandra E; Bilbao, Juan M; Foroud, Tatiana; Ghetti, Bernardino; Nichols, William C; Pankratz, Nathan; Halliday, Glenda; Lesage, Suzanne; Klebe, Stephan; Durr, Alexandra; Duyckaerts, Charles; Brice, Alexis; Giasson, Benoit I; Trojanowski, John Q; Hurtig, Howard I; Tayebi, Nahid; Landazabal, Claudia; Knight, Melanie A; Keller, Margaux; Singleton, Andrew B; Wolfsberg, Tyra G; Sidransky, Ellen
JAMA neurology. 2013;70(6):727-35.
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Full-text held externally
- PMID: 23588557
- UKPMCID: 23588557
- DOI: 10.1001/jamaneurol.2013.1925
Abstract
IMPORTANCE: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. OBJECTIVE: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. SETTING: Eleven centers from sites around the world performing genotyping. PARTICIPANTS: Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. MAIN OUTCOME MEASURES: Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. CONCLUSIONS AND RELEVANCE: Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
Bibliographic metadata
- Nalls, Michael A
- Duran, Raquel
- Lopez, Grisel
- Kurzawa-Akanbi, Marzena
- McKeith, Ian G
- Chinnery, Patrick F
- Morris, Christopher M
- Theuns, Jessie
- Crosiers, David
- Cras, Patrick
- Engelborghs, Sebastiaan
- De Deyn, Peter Paul
- Van Broeckhoven, Christine
- Mann, David M A
- Snowden, Julie
- Pickering-Brown, Stuart
- Halliwell, Nicola
- Davidson, Yvonne
- Gibbons, Linda
- Harris, Jenny
- Sheerin, Una-Marie
- Bras, Jose
- Hardy, John
- Clark, Lorraine
- Marder, Karen
- Honig, Lawrence S
- Berg, Daniela
- Maetzler, Walter
- Brockmann, Kathrin
- Gasser, Thomas
- Novellino, Fabiana
- Quattrone, Aldo
- Annesi, Grazia
- De Marco, Elvira Valeria
- Rogaeva, Ekaterina
- Masellis, Mario
- Black, Sandra E
- Bilbao, Juan M
- Foroud, Tatiana
- Ghetti, Bernardino
- Nichols, William C
- Pankratz, Nathan
- Halliday, Glenda
- Lesage, Suzanne
- Klebe, Stephan
- Durr, Alexandra
- Duyckaerts, Charles
- Brice, Alexis
- Giasson, Benoit I
- Trojanowski, John Q
- Hurtig, Howard I
- Tayebi, Nahid
- Landazabal, Claudia
- Knight, Melanie A
- Keller, Margaux
- Singleton, Andrew B
- Wolfsberg, Tyra G
- Sidransky, Ellen
- 089698, Wellcome Trust, United Kingdom
- 096919, Wellcome Trust, United Kingdom
- 101876, Wellcome Trust, United Kingdom
- 2P30AG010133, NIA NIH HHS, United States
- 2R56NS037167, NINDS NIH HHS, United States
- 5R01NS060113, NINDS NIH HHS, United States
- G-1107, Parkinson's UK, United Kingdom
- G0400074, Medical Research Council, United Kingdom
- G0502157, Medical Research Council, United Kingdom
- G0701075, Medical Research Council, United Kingdom
- G0701441, Medical Research Council, United Kingdom
- G0900652, Medical Research Council, United Kingdom
- G1100479, Medical Research Council, United Kingdom
- G1100540, Medical Research Council, United Kingdom
- M01 RR000645, NCRR NIH HHS, United States
- MC_G0901330, Medical Research Council, United Kingdom
- MC_G1000735, Medical Research Council, United Kingdom
- MR/K000608/1, Medical Research Council, United Kingdom
- NS053488, NINDS NIH HHS, United States
- P30 AG010133, NIA NIH HHS, United States
- P50 AG008702, NIA NIH HHS, United States
- P50AG08702, NIA NIH HHS, United States
- R01 NS036630, NINDS NIH HHS, United States
- R01 NS060113, NINDS NIH HHS, United States
- R56 NS036630, NINDS NIH HHS, United States
- R56NS036630, NINDS NIH HHS, United States
- UL1 RR024156, NCRR NIH HHS, United States
- WT089698, Wellcome Trust, United Kingdom
- Z01 AG000949-02, NIA NIH HHS, United States
- Z99 HG999999, NHGRI NIH HHS, United States
- , Canadian Institutes of Health Research, Canada