Researchers at the Macquarie University Brain Institute and Clinic have helped accelerate the search for disease-causing genes by building new genetic ‘families’.
The team uncovered hundreds of previously unrecognised family connections by analysing the DNA of people with frontotemporal dementia (FTD) and motor neuron disease (MND).
The researchers analysed genetic data from 3524 people with FTD and MND (also known as amyotrophic lateral sclerosis or ALS) from Australia, New Zealand and the United Kingdom. They then identified relatives ranging from siblings to third cousins using a technique called cryptic relatedness analysis.
Lead author Dr Lyndal Henden says these relationships can be difficult to recognise in adult-onset diseases like ALS and FTD because not everyone who carries a genetic variant linked to disease develops symptoms, and family histories may be incomplete.
“Family history does not always tell the whole story in MND and FTD," Dr Henden says. “People who appear unrelated can share DNA inherited from a common ancestor, and bringing these people together into genetic families gives us more information to work with when searching for the causes of disease."
The research published in the journal Brain identified:
793 related pairs within the cohort
More than 30 per cent previously unrecognised relationships.
These hidden relationships allowed the researchers to build 73 new DNA-based family trees from people who had no known genetic explanation for their disease, giving researchers larger families to help track down new disease-linked variants.
“Where we might have had only one person to study, we can now compare affected relatives and prioritise the regions of DNA they inherited from the same ancestor,” said senior author Professor Kelly Williams.
The researchers also mapped shared ancestry around known ALS/FTD genes. This revealed ‘founder’ networks, where people carry the same genetic change (including the known disease-linked SOD1 and C9orf72 genes) because they inherited it from a shared distant ancestor. These networks connected seemingly unrelated families, including people with sporadic disease, across Australia, New Zealand and the United Kingdom.
The study also showed why traditional labels of ‘familial’ and ‘sporadic’ disease do not always capture the underlying genetics. Among people recorded clinically as having sporadic disease, almost 16 per cent of people with FTD and 5.5 per cent of people with ALS were genetically related to another affected person in the cohort. Some genetically related individuals also had different diagnoses, highlighting how shared genetic backgrounds can show up in different ways.
“This kind of analysis helps us find family connections that conventional family histories can miss,” Professor Williams said. “By reconstructing those families genetically, we can make much better use of existing patient cohorts to search for new disease genes and understand why the same inherited genetic background can lead to very different outcomes.”
Brain
Data/statistical analysis
People
Identity-by-descent to resolve reduced penetrance and advance gene discovery in neurodegenerative disease
25-Sep-2026
A.A.C. reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Clene Therapeutics, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, SanoGenetics, Sanofi, Voyager Therapeutics and Wave Pharmaceuticals. A.A.C. declares the following patent: Use of CSF-Neurofilament determinations and CSF-Neurofilament thresholds of prognostic and stratification value with regards to response to therapy in neuromuscular and neurodegenerative diseases. WO2024121173A1. D.B.R. reports consultancies or advisory boards for Biogen, Celosia Therapeutics and Genetic Signatures.