MAPT H1 Haplotype Implicated in ALS Risk, With Genetic Overlap Between ALS and FTD

DNA strand
DNA strand
Investigators sought to identify genetic factors that may contribute to the risk for neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia.

The MAPT H1 haplotype is implicated in the risk for amyotrophic lateral sclerosis (ALS), and there exists a genetic overlap between ALS and diseases of the frontotemporal dementia (FTD) spectrum, according to a study published in JAMA Neurology.

Investigators evaluated genome-wide association studies to determine whether there are frequent genetic variants that drive the risk for ALS. Evaluations were focused on the genetic overlap between ALS and sporadic FTD, FTD with TDP-43 inclusions, Parkinson disease, Alzheimer disease, corticobasal degeneration, and progressive supranuclear palsy (PSP). A total of 124,876 cases and controls were included in the analysis. The primary outcome comprised a list of novel loci as well as their functional pathways among ALS, FTD, PSP, and ALS animal models.

Significant genetic overlap was observed between ALS and FTD at ALS loci rs13302855 (P =.03), rs3849942 (P =.005), and rs4239633 (P =.03). The investigators also observed genetic overlap between ALS and PSP at rs7224296, a loci that tags the MAPT H1 haplotype (P =.045). A total of 22 novel ALS polymorphisms were observed at a conditional false discovery rate FDR P <.05 (ie, rs538622; P =.03 for ALS and FTD), which is associated with modification of BNIP1 gene expression in the brain (35 of 137 female participants; P =.001).

Expression of BNIP1 was found to be decreased in spinal cord motor neurons among patients with ALS (4 controls: mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean [SE] value, 1999 [274.1] AU; P =.02) and in the ALS animal model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P =.002). Additionally, this reduction in BNIP1 gene expression was observed in the brains of patients with PSP (80 controls: mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: mean [SE] value, 6.8 [0.1] AU; β = –0.19; P =.009) or FTD (11 controls: mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: mean [SE] value, 6.53 [0.04] AU; P =.005).

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Considering that the analyses were performed among individuals of European descent, the findings from this study may have limited generalizability.

“By integrating genome-wide association study data with gene expression data from neurodegenerative disease and transgenic mouse models, our multimodal findings implicate the MAPT H1 haplotype in ALS and BNIP1 in the ALS-FTD spectrum,” concluded the investigators.


Karch CM, Wen N, Fan CC, et al; for the International Frontotemporal Dementia (FTD)-Genomics Consortium, International Collaboration for Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium, and International Parkinson’s Disease Genomics Consortium. Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum [published online April 9, 2018]. JAMA Neurol. doi: 10.1001/jamaneurol.2018.0372