Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients

Abstract

It was recently reported that rs1541160 on chromosome 1q24.2 has a marked effect on survival of amyotrophic lateral sclerosis (ALS) patients by influencing KIFAP3 expression. The cohorts used in that study were collected from ALS specialty clinics. We attempted to replicate these findings in a population-based cohort of 504 Italian ALS patients. None of 140 SNPs genotyped within the KIFAP3 locus (including rs1541160) had an effect on survival (log-rank P value for rs1541160 = 0.47) or on gene expression in that region. These data illustrate the complexities associated with analyzing ALS phenotypes for association.

Fig. 1.

Survival from time of symptom onset in a population-based cohort of Italian ALS patients according to rs1541160 status. (A) Kaplan–Meier curves for all 504 patients according to rs1541160 genotype status. (B) Kaplan–Meier curves for all 504 patients according to rs1541160 C allele carrier status. (C) Kaplan–Meier curves restricted to 318 deceased patients according to rs1541160 genotype status. (D) Kaplan–Meier curves for 318 deceased patients according to rs1541160 C allele carrier status. +, censored events.

Fig. 2.

Boxplots illustrating the dose relationship between allele load at rs1541160 and expression of KIFAP3 in human cerebellar tissue samples (n = 143), frontal cortex samples (n = 143), pons samples (n = 141), and temporal cortex samples (n = 144). Binary logarithm of residual expression is shown on the y axis, and rs1541160 genotypes are listed along the x axis. Notably, rs1541160 has no effect on KIFAP3 expression in any of the tested tissue types.

Fig. 3.

Expression quantitative trait loci (eQTL) across the KIFAP3 locus on chromosome 1q24 measured in human cerebellar tissue samples (n = 143), frontal cortex samples (n = 143), pons samples (n = 141), and temporal cortex samples (n = 144). In this analysis the allelic load at each of the 1,004 polymorphisms across the locus is tested for association with transcript levels of each gene within the locus. The results of the analysis are shown as log transformed P values (based on Cochran–Armitage test for trend) that are color-coded to match the transcript of interest. Notably, genotypes across this locus are not associated with KIFAP3 (blue), SCYL3 (green), or SCYL1BP1 (red) expression levels. Only transcripts expressed in each tissue are displayed. SCYL3 expression was not detected in cerebellar tissue. The dashed horizontal line represents the threshold for genome-wide significance (8.85 × 10⁻⁸), and the dotted horizontal line represents the threshold for significance correcting for 1,004 SNPs within the locus [0.05/(1,004 × 4 tissues) = 1.25 × 10⁻⁵]. The vertical black arrow indicates the position of rs1541160.