Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.
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Marriott Heather, Spargo Thomas P, Al Khleifat Ahmad, Andersen Peter M, Başak Nazli A, Cooper-Knock Johnathan, Corcia Philippe, Couratier Philippe, de Carvalho Mamede, Drory Vivian, Gotkine Marc, Landers John E, McLaughlin Russell, Pardina Jesús S Mora, Morrison Karen E, Pinto Susana, Shaw Christopher E, Shaw Pamela J, Silani Vincenzo, Ticozzi Nicola, van Damme Philip, van den Berg Leonard H, Vourc'h Patrick, Weber Markus, Veldink Jan H, Project MinE ALS Sequencing Consortium, Dobson Richard J, Schwab Patrick, Al-Chalabi Ammar, Iacoangeli Alfredo
Аннотация
METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data.
RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation.
INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.