Genetic Modifiers of ALS: The Impact of Chromogranin B P413L in a Bulgarian ALS Cohort

Abstract

This study investigated the role of the CHGB P413L variant (rs742710) in sporadic amyotrophic lateral sclerosis (sALS) within the Bulgarian population. We analyzed 150 patients with sALS (85 male and 65 female) for the presence of this variant, its potential impact on disease susceptibility, and age of onset. Genotyping was performed using PCR amplification and direct Sanger sequencing. Statistical analyses included comparisons with control data from GnomAD v2.1.1, one-way ANOVA, and Kaplan-Meier survival analysis. Results revealed a higher frequency of the minor T allele in patients with sALS compared to all control groups and a statistically significant increase in carrier genotypes compared to non-Finnish Europeans (χ² = 15.4572, p = 0.000440). However, the impact on age of onset was less clear, with no statistically significant differences observed across genotypes or between carriers and non-carriers of the T allele. Kaplan-Meier analysis suggested a potential 2.5-year-earlier onset in T allele carriers, but the small sample size of carriers limits the reliability of this finding. Our study provides evidence for an association between the CHGB P413L variant and sALS susceptibility in the Bulgarian population, while its effect on age of onset remains uncertain, highlighting the need for further research in larger, diverse cohorts.

Keywords: ALS; CHGB; P413L.

Figure 1

Bar charts depicting the allele frequencies between patients with ALS (blue) and control groups (orange). The minor allele of the rs742710 variant is present with a slightly elevated frequency in the patient group against all tested control populations.

Figure 2

Bar charts depicting the allele frequencies between patients with ALS (blue) and control groups (orange). The carrier genotypes C/T and T/T for the rs742710 variant are slightly elevated compared to NFE controls and non-neuro individuals, while only the homozygous T/T genotype has a higher frequency compared to Bulgarian controls and non-neuro individuals.

Figure 3

Kaplan–Meier survival curves for onset based on genotype for the entire patient cohort (top) and split by sex (bottom). Heterozygous carriers (orange) show an earlier onset regardless of sex, while homozygous T/T carriers (red) display an earlier onset only in males compared to controls (green).

Figure 4

Kaplan–Meier survival curves for onset based on carrier status for the minor allele for the entire patient cohort (top) and split by sex (bottom). Carriers of the T allele (red) present with an earlier onset of the disease, with 2.43 years for the entire cohort, 2.57 years for males and 0.43 years for females compared to controls (green).