A major international study has found that one in four people with motor neuron disease (MND) has an identifiable genetic cause. This is a significant increase from previous estimates, and it opens the door to targeted treatments for a larger proportion of people living with the condition.
The study is the largest genetic analysis of MND ever conducted. Published today in Nature Genetics, it draws on genetic data from more than 18,000 people with MND and over 200,000 controls across 22 research cohorts worldwide. Around 2,000 of the samples came from the UK MND DNA Bank, led by King’s College London — a partner institution of the UK MND Research Institute. Researchers from King’s and the University of Sheffield, also a partner institution, are among the co-authors.
The findings matter because many of the most promising treatments in development for MND target a specific gene. Gene-silencing therapies have already produced approved treatments for people whose MND is caused by variants in SOD1 and FUS. Until now, researchers could identify a genetic cause in only around one in eight people with MND. This study substantially increases that figure.
The team identified four new candidate risk genes — YKT6, HTR3C, GBGT1 and KNTC1 — and strongly confirmed three genes that researchers had previously flagged but lacked sufficient evidence to act on: ARPP21, DNAJC7 and CFAP410. A variant in ARPP21 is associated with earlier disease onset and a shorter disease course — an important finding for understanding why MND progresses differently in different people and for deciding which genes to prioritise as treatment targets.
The results also support the view that MND often involves several rare genetic variants combining to increase risk, rather than a single faulty gene. The more of these variants someone carries, the greater their risk — a complex but increasingly mappable picture.
Professor Ammar Al-Chalabi, co-Director of the UK MND Research Institute and Professor of Neurology and Complex Disease Genetics at King’s College London, said: “This study appreciably increases our knowledge of what causes MND, showing that it has a significant genetic component in about a quarter of people with the disease, regardless of family history. That means everyone presenting with symptoms should be offered genetic testing, and this increased knowledge improves the chances of developing an effective treatment.”
Researchers at the University Medical Centre Utrecht led the study, with collaborators spanning Europe, North America and Australia.
Read the full paper in Nature Genetics.
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