Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk.

We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at P approximately 10(-8)). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2) > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.

[1]  K. Blennow,et al.  A survey of ABCA1 sequence variation confirms association with dementia , 2009, Human mutation.

[2]  E. Sonnhammer,et al.  Global networks of functional coupling in eukaryotes from comprehensive data integration. , 2009, Genome research.

[3]  Christian von Mering,et al.  STRING 8—a global view on proteins and their functional interactions in 630 organisms , 2008, Nucleic Acids Res..

[4]  R. Tanzi,et al.  Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses , 2008, Nature Reviews Neuroscience.

[5]  M. Stephens,et al.  High-Resolution Mapping of Expression-QTLs Yields Insight into Human Gene Regulation , 2008, PLoS genetics.

[6]  A. Myers,et al.  Transcriptome-Wide Assessment of Human Brain and Lymphocyte Senescence , 2008, PloS one.

[7]  S. Horvath,et al.  Variations in DNA elucidate molecular networks that cause disease , 2008, Nature.

[8]  R. Collins,et al.  Newly identified loci that influence lipid concentrations and risk of coronary artery disease , 2008, Nature Genetics.

[9]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[10]  D. Stephan,et al.  A survey of genetic human cortical gene expression , 2007, Nature Genetics.

[11]  Hagit Shatkay,et al.  F-SNP: computationally predicted functional SNPs for disease association studies , 2007, Nucleic Acids Res..

[12]  L. Liang,et al.  A genome-wide association study of global gene expression , 2007, Nature Genetics.

[13]  J. Danesh,et al.  Association of apolipoprotein E genotypes with lipid levels and coronary risk. , 2007, JAMA.

[14]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[15]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[16]  Winnie S. Liang,et al.  GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers , 2007, Neuron.

[17]  A. Barabasi,et al.  The human disease network , 2007, Proceedings of the National Academy of Sciences.

[18]  P. Deyn,et al.  Association study of cholesterol-related genes in Alzheimer’s disease , 2007, Neurogenetics.

[19]  C. Carter,et al.  Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis , 2007, Neurochemistry International.

[20]  E. Boerwinkle,et al.  Evidence for Consistent Intragenic and Intergenic Interactions between SNP Effects in the APOA1/C3/A4/A5 Gene Cluster , 2006, Human Heredity.

[21]  Yohei Katoh,et al.  Recruitment of clathrin onto endosomes by the Tom1-Tollip complex. , 2006, Biochemical and biophysical research communications.

[22]  John D. Storey,et al.  A network-based analysis of systemic inflammation in humans , 2005, Nature.

[23]  L. Fratiglioni,et al.  Complete ascertainment of dementia in the Swedish Twin Registry: the HARMONY study , 2005, Neurobiology of Aging.

[24]  Terho Lehtimäki,et al.  The association of the apolipoprotein E gene promoter polymorphisms and haplotypes with serum lipid and lipoprotein concentrations. , 2005, Atherosclerosis.

[25]  M. Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[26]  Henrik Zetterberg,et al.  APOE ε4 allele is associated with reduced cerebrospinal fluid levels of Aβ42 , 2004, Neurology.

[27]  J. Palmgren,et al.  Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to β‐amyloid metabolism , 2004, Human mutation.

[28]  G. Mcclearn,et al.  Association between depressed mood in the elderly and a 5‐HTR2A gene variant , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[29]  P. Lichtenstein,et al.  The Swedish Twin Registry: a unique resource for clinical, epidemiological and genetic studies , 2002, Journal of internal medicine.

[30]  K. Sneppen,et al.  Specificity and Stability in Topology of Protein Networks , 2002, Science.

[31]  G. Mcclearn,et al.  Gender and health: a study of older unlike-sex twins. , 2002, The journals of gerontology. Series B, Psychological sciences and social sciences.

[32]  K. Blennow,et al.  Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample. , 1999, Neurology.

[33]  J. Poirier,et al.  Apolipoprotein E isoform-specific reduction of extracellular amyloid in neuronal cultures. , 1999, Brain research. Molecular brain research.

[34]  H. Vanderstichele,et al.  Towards an earlier diagnosis of Alzheimer's disease. , 1998, Journal of biotechnology.

[35]  W. Quax,et al.  Alzheimer tau test and detergent cellulase made by genetic engineering (no 9 in a series of articles to promote a better understanding of the use of genetic engineering) , 1998 .

[36]  B Johansson,et al.  Substantial genetic influence on cognitive abilities in twins 80 or more years old. , 1997, Science.

[37]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[38]  K. Blennow,et al.  Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? , 1995, Molecular and chemical neuropathology.

[39]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[40]  M. Pericak-Vance,et al.  Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Gauthier,et al.  Apolipoprotein E polymorphism and Alzheimer's disease , 1993, The Lancet.

[42]  P. Diggle,et al.  Modelling multivariate binary data with alternating logistic regressions , 1993 .

[43]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[44]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[46]  G. Mcclearn,et al.  Swedish early separated twins: identification and characterization. , 1984, Acta geneticae medicae et gemellologiae.

[47]  Lois Oakes,et al.  HUMAN DISEASE , 1957, The Ulster Medical Journal.

[48]  R. Collins,et al.  Common variants at 30 loci contribute to polygenic dyslipidemia , 2009, Nature Genetics.

[49]  Christian Gieger,et al.  Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts , 2009, Nature Genetics.

[50]  Nick C Fox,et al.  Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease , 2009 .

[51]  Winnie S. Liang,et al.  GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. , 2007, Neuron.

[52]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[53]  Gustav Schonfeld,et al.  Genetic variants of ApoE account for variability of plasma low-density lipoprotein and apolipoprotein B levels in FHBL. , 2005, Atherosclerosis.

[54]  K. Blennow,et al.  APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42. , 2004, Neurology.

[55]  M Kanehisa,et al.  Organizing and computing metabolic pathway data in terms of binary relations. , 1997, Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing.

[56]  J. Hardy,et al.  Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. , 1996, Nature medicine.