Mizanur Khondoker1, Stephen Newhouse1, Eric Westman2, J-Sebastian Muehlboeck2, Patrizia Mecocci3, Bruno Vellas4, Magda Tsolaki4, Iwona Kłoszewska5, Hilkka Soininen6, Simon Lovestone7, Richard Dobson8, Andrew Simmons8. 1. King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom King's College London, Institute of Psychiatry, Psychology & Neuroscience, Department of Biostatistics, London, United Kingdom. 2. King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom Departments of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. 3. Institute of gerontology and Geriatrics, University of Perugia, Perugia, Italy. 4. INSERM U 558, University of Toulouse, Toulouse, France. 5. Medical University of Lodz, Lodz, Poland. 6. Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. 7. Department of Psychiatry, University of Oxford, United Kingdom. 8. King's College London, Institute of Psychiatry, Psychology & Neuroscience and NIHR Biomedical Research Centre for Mental Health, London, United Kingdom NIHR Biomedical Research Unit Dementia, London, United Kingdom.
Abstract
BACKGROUND: Alzheimer's disease (AD) is a highly heritable disease, but until recently few replicated genetic markers have been identified. Markers identified so far are likely to account for only a tiny fraction of the heritability of AD and many more genetic risk alleles are thought to be undiscovered. OBJECTIVE: Identifying genetic markers for AD using combined analysis of genetics and brain imaging data. METHODS: Imaging quantitative trait loci (iQTLs) has recently emerged as an interesting research area for linking genetics of brain changes to AD. We consider a genome-wide association scan of 109 brain-wide regional imaging phenotypes to identify genetic susceptibility loci for AD from a combined set of 1,045 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the AddNeuroMed studies. We use one-SNP-at-a-time as well as multi-SNP Hyperlasso based iQTL methods for the analysis. RESULTS: We identified several novel markers associated with AD, namely HOMER2 (rs1256429; intronic, p = 8.7 × 10⁻¹⁰), EOMES (rs2724509; flanking), JAM2 (rs2829841; intronic), and WEE1 (rs10770042; coding). The SNP rs1256429 (HOMER2) was one of the top hits in Hyperlasso as well as in the single-SNP analysis showing an association with the volume of the right thalamus and AD, a brain region reported to be linked with AD in several studies. CONCLUSION: We believe that the markers identified in this study are novel additions to the existing list of genetic variants associated with AD which can be validated in future replicated studies.
BACKGROUND: Alzheimer's disease (AD) is a highly heritable disease, but until recently few replicated genetic markers have been identified. Markers identified so far are likely to account for only a tiny fraction of the heritability of AD and many more genetic risk alleles are thought to be undiscovered. OBJECTIVE: Identifying genetic markers for AD using combined analysis of genetics and brain imaging data. METHODS: Imaging quantitative trait loci (iQTLs) has recently emerged as an interesting research area for linking genetics of brain changes to AD. We consider a genome-wide association scan of 109 brain-wide regional imaging phenotypes to identify genetic susceptibility loci for AD from a combined set of 1,045 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the AddNeuroMed studies. We use one-SNP-at-a-time as well as multi-SNP Hyperlasso based iQTL methods for the analysis. RESULTS: We identified several novel markers associated with AD, namely HOMER2 (rs1256429; intronic, p = 8.7 × 10⁻¹⁰), EOMES (rs2724509; flanking), JAM2 (rs2829841; intronic), and WEE1 (rs10770042; coding). The SNP rs1256429 (HOMER2) was one of the top hits in Hyperlasso as well as in the single-SNP analysis showing an association with the volume of the right thalamus and AD, a brain region reported to be linked with AD in several studies. CONCLUSION: We believe that the markers identified in this study are novel additions to the existing list of genetic variants associated with AD which can be validated in future replicated studies.
Entities:
Keywords:
Alzheimer's disease; genome wide association study; imaging quantitative trait loci; magnetic resonance imaging; mild cognitive impairment
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