NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Abstract

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1

RVB analysis of FALS exomes. (a) RVB analyses of 1,022 index FALS cases and 7,315 controls for 10 known ALS genes, to assess 308 different combinations of MAF and functional prediction filters (Supplementary Table 1). The set of analysis parameters achieving the highest sensitivity for known ALS genes was identified as that achieving the highest area under the curve (AUC) in a plot of sensitivity (proportion of training genes achieving significance) across an increasing minimum P-value threshold. Dotted vertical line denotes Bonferroni-corrected P value for exome-wide significance. (b) Extension of the highest performing known gene-trained analysis to the entire exome. Threshold for exome-wide significance is denoted by the dotted red line. λ, observed genomic inflation factor. ‘Obs’ describes the P-value distribution for the observed data. ‘Exp’ describes the P-value distribution under null expectation.

Figure 2

Replication analysis of NEK1 p.Arg261His. NEK1 p.Arg261His genotypes were ascertained for 1,022 FALS samples, 6,172 SALS samples and 11,732 controls. The SALS cohort was divided into seven geographically based case–control strata. Logistic regression was used to conduct tests of allelic association for all subcohorts and was followed by a fixed-effects meta-analysis. In the distribution of OR estimates across study cohorts (right), vertical dotted line denotes OR estimated under meta-analysis. CI, confidence interval.