Investigating the influence of <em>ABCA7</em> polymorphism on the lipidome in the Busselton Healthy Ageing Study (BHAS) — The Association Specialists
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Investigating the influence of ABCA7 polymorphism on the lipidome in the Busselton Healthy Ageing Study (BHAS) (22218)

Luke Whiley 1 2 3 , Samantha SY Lee 4 , David A Mackey 4 5 , Bu B Yeap 6 , Jennie Hui 7 8 , Michael L Hunter 7 8 , Hamid R Sohrabi 1 9 , Elaine Holmes 1 3
  1. Health Futures Institute, Murdoch University, Murdoch, WA, Australia
  2. Australian National Phenome Centre, Murdoch University, Murdoch, Western Australia, Australia
  3. Centre for Computational and Systems Medicine, Murdoch University, Murdoch, Western Australia, Australia
  4. Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia
  5. School of Medicine, University of Tasmania, Hobart, Tasmania, Australia
  6. Medical School, University of Western Australia, Perth, Western Australia, Australia
  7. School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia
  8. Busselton Population Medical Research Institute, Busselton, Western Australia, United Kingdom
  9. Centre for Healthy Ageing, Murdoch University, Murdoch, Western Australia, Australia

Single nucleotide polymorphisms (SNPs) in the ABCA7 gene region have been reported to elevate the risk of Alzheimer’s disease (AD) by ~20%. However, their impact on fundamental biology remains unknown, as they do not appear to affect downstream protein function or metabolism. To elucidate any mechanistic links to disease, the impact of these polymorphisms on the biological system must be fully determined prior to disease onset.

Therefore, ABCA7 SNP and metabolic phenotyping data were collected from 1953 individuals from the Busselton Healthy Ageing Study (BHAS) at the Australian National Phenome Centre (Murdoch University) using mass spectrometry lipidomics1. Data were acquired from samples collected at two timepoints, approximately six years apart. Baseline data underwent linear regression modelling against three ABCA7 SNPs (rs3764650, rs4147929, and rs3752246) in the BHAS population, which have been associated with elevated AD risk in the literature.

Following quality control, the lipidomic dataset consisted of 860 lipid features. The minor allele frequency of the three ABCA7 SNPs in the BHAS dataset ranged from 308-579 (heterozygous) and 17-69 (homozygous). Linear regression modelling of baseline data versus each lipid feature revealed a lipidomic signature indicative of perturbations in lactosylceramide metabolism for individuals carrying ABCA7 polymorphisms associated with elevated AD risk. 

These results align with previous reports of lactosylceramide perturbations linked to ABCA7 polymorphism in independent cohorts2. Future work will focus on further elucidating the lipidomic signature of ABCA7 polymorphism, including age-related trajectories and associations with additional AD risk factors such as biological sex, APOE status, BMI, and cognitive function.

 

  1. Comprehensive Lipidomic Workflow for Multicohort Population Phenotyping Using Stable Isotope Dilution Targeted Liquid Chromatography-Mass Spectrometry, Ryan M et al. J Proteome Res. 2023 May 5;22(5):1419-1433. doi: 10.1021/acs.jproteome.2c00682.
  2. Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease, Dehghan A et al. Proc Natl Acad Sci U S A. 2022 Oct 25;119(43):e2206083119. doi: 10.1073/pnas.2206083119.