Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis

Michael A. Van Es*, Helenius J. Schelhaas, Paul W.J. Van Vught, Nicola Ticozzi, Peter M. Andersen, Ewout J.N. Groen, Claudia Schulte, Hylke M. Blauw, Max Koppers, Frank P. Diekstra, Katsumi Fumoto, Ashley Lyn Leclerc, Pamela Keagle, Bastiaan R. Bloem, Hans Scheffer, Bart F.L. Van Nuenen, Marka Van Blitterswijk, Wouter Van Rheenen, Anne Marie Wills, Patrick P. LoweGuo Fu Hu, Wenhao Yu, Hiroko Kishikawa, David Wu, Rebecca D. Folkerth, Claudio Mariani, Stefano Goldwurm, Gianni Pezzoli, Philip Van Damme, Robin Lemmens, Caroline Dahlberg, Anna Birve, Rubén Fernández-Santiago, Stefan Waibel, Christine Klein, Markus Weber, Anneke J. Van Der Kooi, Marianne De Visser, Dagmar Verbaan, Jacobus J. Van Hilten, Peter Heutink, Eric A.M. Hennekam, Edwin Cuppen, Daniela Berg, Robert H. Brown, Vincenzo Silani, Thomas Gasser, Albert C. Ludolph, Wim Robberecht, Roel A. Ophoff, Jan H. Veldink, R. Jeroen Pasterkamp, Paul I.W. De Bakker, John E. Landers, Bart P. Van De Warrenburg, Leonard H. Van Den Berg

*Corresponding author for this work
91 Citations (Scopus)


Objective: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. 

Methods: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. 

Results: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10 -6 for ALS and p = 4.3 × 10 -5 for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.

Interpretation: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

Original languageEnglish
JournalAnnals of Neurology
Issue number6
Pages (from-to)964-973
Number of pages10
Publication statusPublished - 01.12.2011


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