Poster Presentation GENEMAPPERS 2024

The power of identity-by-descent analysis for disease-gene discovery in neurodegenerative diseases (#59)

Lyndal Henden 1 , Isabel Li 1 , Emily P McCann 1 , Simon Topp 2 , Alfredo Iacoangeli 2 , Emma L Scotter 3 4 , Natalie Grima 1 , Carol Dobson-Stone 5 , Miran Mrkela 3 4 , John B Kwok 5 , Glenda Halliday 5 , Roger Pamphlett 6 , Amar Al-Chalabi 2 , Richard H Roxburgh 3 7 8 , Tian Lin 9 , Nigel G Laing 10 , Merrilee Needham 11 12 13 , David Schultz 14 , Susan Mathers 15 , Steve Vucic 16 , Matthew Kiernan 5 , Robert Henderson 17 18 , Anjali K Henders 9 19 , Garth A Nicholson 1 20 21 , Dominic B Rowe 1 , Bradley Smith 2 , Ian P Blair 1 , Kelly L Williams 1
  1. Macquarie University Motor Neuron Disease Research Centre, Macquarie University, Sydney, NSW, Australia
  2. Maurice Wohl Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience King’s College London, London, United Kingdom
  3. The Centre for Brain Research, Faculty of Science, University of Auckland, Auckland, New Zealand
  4. School of Biological Sciences, University of Auckland, Auckland, New Zealand
  5. Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia
  6. RPAH Department of Neuropathology, and School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia
  7. Department of Neurology, Auckland City Hospital, Auckland, New Zealand
  8. Neurogenetics Research Clinic, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
  9. Institute for Molecular Bioscience, University of Queensland, QLD, Australia
  10. Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA, Australia
  11. Fiona Stanley Hospital, Perth, WA, Australia
  12. Notre Dame University, Freemantle, WA, Australia
  13. Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
  14. Neurology Department and MND Clinic, Flinders Medical Centre, Adelaide, SA, Australia
  15. Calvary Health Care Bethlehem, Parkdale, VIC, Australia
  16. Sydney Medical School Westmead, University of Sydney, Sydney, NSW, Australia
  17. Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
  18. Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
  19. Cooperative Research Centre for Living with Autism, Long Pocket, QLD, Australia
  20. Molecular Medicine Laboratory, Concord Hospital, Sydney, NSW, Australia
  21. ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, NSW, Australia

Most of us know our first cousins, aunts/uncles, and grandparents, however our knowledge of more distant relationships in our genealogy is often incomplete. This extends to medical history within our extended family, especially concerning late-onset diseases that might present in distant relatives, including our primary focus of two overlapping neurodegenerative diseases: motor neuron disease (MND) and frontotemporal dementia (FTD).

Genetic factors are the only proven causes of MND and FTD, yet only ~15% of MND patients and ~30% of FTD patients have an identified genetic cause of disease. The binary classification of patients, based on presence/absence of a family history of MND and/or FTD, directly influences the methodologies chosen to find disease-linked genetic variants. Linkage analysis has been successful in disease-gene identification in highly-penetrant MND or FTD families, while genome-wide association studies (GWAS) have uncovered risk alleles in sporadic patients. However, for smaller reduced-penetrance families or cohorts lacking statistical power for GWAS, alternative methods are required.

We have used identity-by-descent (IBD) analysis as an alternative method for gene discovery in a large integrated cohort of both hereditary and sporadic MND and FTD cases. Our rationale is that IBD analysis can uncover distant unknown relatives who are also affected with MND and/or FTD, to effectively join branches of a family pedigree. IBD results can be further leveraged to pinpoint inherited genomic regions as putative disease loci to search for disease-linked variants using whole-genome sequencing.

Our IBD analysis on SNP genotype data from >3,000 MND and FTD patients from Australia, New Zealand and the United Kingdom has created more than 40 ‘new’ families for gene discovery efforts; linked hereditary and sporadic patients with a known disease-causing variant; and successfully uncovered the genetic cause of disease in 15 MND patients; highlighting the power of IBD analysis in gene discovery.