title: Linking Genetics of Brain Changes to Alzheimer's Disease: Sparse Whole Genome Association Scan of Regional MRI Volumes in the ADNI and AddNeuroMed Cohorts.
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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Mizanur
authors: M
authors: Khondoker
authors: 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.
authors: Stephen
authors: S
authors: Newhouse
authors: 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.
authors: Eric
authors: E
authors: Westman
authors: 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.
authors: J-Sebastian
authors: JS
authors: Muehlboeck
authors: Institute of gerontology and Geriatrics, University of Perugia, Perugia, Italy.
authors: Patrizia
authors: P
authors: Mecocci
authors: INSERM U 558, University of Toulouse, Toulouse, France.
authors: Bruno
authors: B
authors: Vellas
authors: INSERM U 558, University of Toulouse, Toulouse, France.
authors: Magda
authors: M
authors: Tsolaki
authors: Medical University of Lodz, Lodz, Poland.
authors: Iwona
authors: I
authors: Kłoszewska
authors: Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors: Hilkka
authors: H
authors: Soininen
authors: Department of Psychiatry, University of Oxford, United Kingdom.
authors: Simon
authors: S
authors: Lovestone
authors: 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.
authors: Richard
authors: R
authors: Dobson
authors: 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.
authors: Andrew
authors: A
authors: Simmons
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D000072233:Homer Scaffolding Proteins; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012737:Sex Factors; D020825:T-Box Domain Proteins / Q000235:genetics; D062765:Junctional Adhesion Molecule B
chemical_list: D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D000072233:Homer Scaffolding Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D020825:T-Box Domain Proteins; C491199:EOMES protein, human; C411887:JAM2 protein, human; D062765:Junctional Adhesion Molecule B; C499349:WEE1 protein, human
keywords: Alzheimer's disease; genome wide association study; imaging quantitative trait loci; magnetic resonance imaging; mild cognitive impairment