Sex differences in the prevalence of genetic mutations in FTD and ALS: A meta-analysis.

Abstract

To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-chromosome 9 open reading frame 72 (<i>C9orf72</i>), progranulin (<i>GRN</i>), or microtubule-associated protein tau (<i>MAPT</i>)-in patients clinically diagnosed with these conditions. MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models. Thirty-two articles reporting 12,784 patients with ALS (including 1,244 <i>C9orf72</i> mutation carriers) revealed a higher prevalence of female patients with <i>C9orf72-</i>related ALS (RR 1.16, 95% CI 1.04-1.29). Twenty-three articles reporting 5,320 patients with FTD (including 488 <i>C9orf72</i> mutation carriers) revealed no sex differences in <i>C9orf72</i>-related FTD (RR 0.95, 95% CI 0.81-1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 <i>GRN</i> mutation carriers) revealed a higher prevalence of female patients with <i>GRN-</i>related FTD (RR 1.33, 95% CI 1.09-1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 <i>MAPT</i> mutation carriers) revealed no sex difference in <i>MAPT-</i>related FTD (RR 1.21, 95% CI 0.95-1.55). Higher female prevalence of <i>C9orf72</i> hexanucleotide repeat expansions in ALS and <i>GRN</i> mutations in FTD suggest that sex-related risk factors might moderate <i>C9orf72</i> and <i>GRN-</i>mediated phenotypic expression.