-
Views
-
Cite
Cite
Wouter van Rheenen, Frank P. Diekstra, Leonard H. van den Berg, Jan H. Veldink, Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?, Brain, Volume 137, Issue 12, December 2014, Page e313, https://doi.org/10.1093/brain/awu299
Close - Share Icon Share
Extract
Sir,
A recent study by Bannwarth et al. (2014) in Brain identified a novel mutation (c.176C > T; p.Ser59Leu) in the CHCHD10 gene that segregates in a family presenting with ataxia, myopathy, hearing loss as well as motor neuron disease and frontotemporal dementia (FTD). Furthermore they identified a second family with ALS/FTD harbouring the identical mutation making this a gene of interest in the pathogenesis of ALS/FTD. For this reason we read with great interest the letter by Müller et al. (2014) that describes the identification of two novel variants in CHCHD10 in three pedigrees with familial amyotrophic lateral sclerosis (ALS). The authors state that their findings provide strong support for CHCHD10 being a novel ALS gene. Although their findings are highly interesting and their conclusion is appealing, we feel obliged to make several remarks concerning the genetic evidence provided to support this statement.
The definition of genetic evidence, driven by the problem of non-replicating findings, is a matter of concern over the past years and has led to multiple consensus definitions for different study designs (reviewed by Pulit et al., 2014). A landmark paper published nearly 20 years ago defined segregation of the gene with the studied phenotype within a pedigree resulting in a LOD score ≥ 3 as robust genetic evidence (Lander and Kruglyak, 1995). For genome-wide association studies the problem of multiple testing was overcome by adopting a significance threshold of P < 5 × 10−8 on a genome-wide level and P < 5 × 10−7 on an exome-wide level (Dudbridge et al., 2008; Pe’er et al., 2008; Do et al., 2012). Although these measures might seem conservative and are hard to meet in smaller studies, relaxing these thresholds in the past has led to an unfortunately high number of false positive associations: of 166 associations with more than two follow-up studies, only six (3.6%) replicated (Hirschhorn et al., 2002).
