ALBERT

Description: Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected--including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas--the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jakobsson, Mattias -- Scholz, Sonja W -- Scheet, Paul -- Gibbs, J Raphael -- VanLiere, Jenna M -- Fung, Hon-Chung -- Szpiech, Zachary A -- Degnan, James H -- Wang, Kai -- Guerreiro, Rita -- Bras, Jose M -- Schymick, Jennifer C -- Hernandez, Dena G -- Traynor, Bryan J -- Simon-Sanchez, Javier -- Matarin, Mar -- Britton, Angela -- van de Leemput, Joyce -- Rafferty, Ian -- Bucan, Maja -- Cann, Howard M -- Hardy, John A -- Rosenberg, Noah A -- Singleton, Andrew B -- G0701075/Medical Research Council/United Kingdom -- MR/K01417X/1/Medical Research Council/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2008 Feb 21;451(7181):998-1003. doi: 10.1038/nature06742.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Computational Medicine and Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288195" target="_blank"〉PubMed〈/a〉

Description: Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications 〉100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Walsh, Tom -- McClellan, Jon M -- McCarthy, Shane E -- Addington, Anjene M -- Pierce, Sarah B -- Cooper, Greg M -- Nord, Alex S -- Kusenda, Mary -- Malhotra, Dheeraj -- Bhandari, Abhishek -- Stray, Sunday M -- Rippey, Caitlin F -- Roccanova, Patricia -- Makarov, Vlad -- Lakshmi, B -- Findling, Robert L -- Sikich, Linmarie -- Stromberg, Thomas -- Merriman, Barry -- Gogtay, Nitin -- Butler, Philip -- Eckstrand, Kristen -- Noory, Laila -- Gochman, Peter -- Long, Robert -- Chen, Zugen -- Davis, Sean -- Baker, Carl -- Eichler, Evan E -- Meltzer, Paul S -- Nelson, Stanley F -- Singleton, Andrew B -- Lee, Ming K -- Rapoport, Judith L -- King, Mary-Claire -- Sebat, Jonathan -- HD043569/HD/NICHD NIH HHS/ -- M01 RR000046/RR/NCRR NIH HHS/ -- MH061355/MH/NIMH NIH HHS/ -- MH061464/MH/NIMH NIH HHS/ -- MH061528/MH/NIMH NIH HHS/ -- NS052108/NS/NINDS NIH HHS/ -- R01 HD043569/HD/NICHD NIH HHS/ -- RR000046/RR/NCRR NIH HHS/ -- RR025014/RR/NCRR NIH HHS/ -- U01 MH061355/MH/NIMH NIH HHS/ -- U01 MH061464/MH/NIMH NIH HHS/ -- U01 MH061528/MH/NIMH NIH HHS/ -- U24 NS052108/NS/NINDS NIH HHS/ -- UL1 RR025014/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2008 Apr 25;320(5875):539-43. doi: 10.1126/science.1155174. Epub 2008 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18369103" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singleton, Andrew B -- New York, N.Y. -- Science. 2014 Jan 31;343(6170):497-8. doi: 10.1126/science.1250172.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24482474" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singleton, A B -- Farrer, M -- Johnson, J -- Singleton, A -- Hague, S -- Kachergus, J -- Hulihan, M -- Peuralinna, T -- Dutra, A -- Nussbaum, R -- Lincoln, S -- Crawley, A -- Hanson, M -- Maraganore, D -- Adler, C -- Cookson, M R -- Muenter, M -- Baptista, M -- Miller, D -- Blancato, J -- Hardy, J -- Gwinn-Hardy, K -- New York, N.Y. -- Science. 2003 Oct 31;302(5646):841.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. singleta@mail.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14593171" target="_blank"〉PubMed〈/a〉

Description: Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-beta precursor protein (APP) and extracellular Abeta42 and Abeta40 (the 42- and 40-residue isoforms of the amyloid-beta peptide), and knockdown of PLD3 leads to a significant increase in extracellular Abeta42 and Abeta40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050701/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050701/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cruchaga, Carlos -- Karch, Celeste M -- Jin, Sheng Chih -- Benitez, Bruno A -- Cai, Yefei -- Guerreiro, Rita -- Harari, Oscar -- Norton, Joanne -- Budde, John -- Bertelsen, Sarah -- Jeng, Amanda T -- Cooper, Breanna -- Skorupa, Tara -- Carrell, David -- Levitch, Denise -- Hsu, Simon -- Choi, Jiyoon -- Ryten, Mina -- UK Brain Expression Consortium -- Hardy, John -- Trabzuni, Daniah -- Weale, Michael E -- Ramasamy, Adaikalavan -- Smith, Colin -- Sassi, Celeste -- Bras, Jose -- Gibbs, J Raphael -- Hernandez, Dena G -- Lupton, Michelle K -- Powell, John -- Forabosco, Paola -- Ridge, Perry G -- Corcoran, Christopher D -- Tschanz, Joann T -- Norton, Maria C -- Munger, Ronald G -- Schmutz, Cameron -- Leary, Maegan -- Demirci, F Yesim -- Bamne, Mikhil N -- Wang, Xingbin -- Lopez, Oscar L -- Ganguli, Mary -- Medway, Christopher -- Turton, James -- Lord, Jenny -- Braae, Anne -- Barber, Imelda -- Brown, Kristelle -- Alzheimer's Research UK Consortium -- Passmore, Peter -- Craig, David -- Johnston, Janet -- McGuinness, Bernadette -- Todd, Stephen -- Heun, Reinhard -- Kolsch, Heike -- Kehoe, Patrick G -- Hooper, Nigel M -- Vardy, Emma R L C -- Mann, David M -- Pickering-Brown, Stuart -- Kalsheker, Noor -- Lowe, James -- Morgan, Kevin -- David Smith, A -- Wilcock, Gordon -- Warden, Donald -- Holmes, Clive -- Pastor, Pau -- Lorenzo-Betancor, Oswaldo -- Brkanac, Zoran -- Scott, Erick -- Topol, Eric -- Rogaeva, Ekaterina -- Singleton, Andrew B -- Kamboh, M Ilyas -- St George-Hyslop, Peter -- Cairns, Nigel -- Morris, John C -- Kauwe, John S K -- Goate, Alison M -- 081864/Wellcome Trust/United Kingdom -- 089698/Wellcome Trust/United Kingdom -- 089703/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- 1R01AG041797/AG/NIA NIH HHS/ -- 5U24AG026395/AG/NIA NIH HHS/ -- AG005133/AG/NIA NIH HHS/ -- AG023652/AG/NIA NIH HHS/ -- AG030653/AG/NIA NIH HHS/ -- AG041718/AG/NIA NIH HHS/ -- AG07562/AG/NIA NIH HHS/ -- G0802189/Medical Research Council/United Kingdom -- G0802462/Medical Research Council/United Kingdom -- G0901254/Medical Research Council/United Kingdom -- G1100695/Medical Research Council/United Kingdom -- K01 AG046374/AG/NIA NIH HHS/ -- MC_G1000734/Medical Research Council/United Kingdom -- NIH P50 AG05681/AG/NIA NIH HHS/ -- NIH R01039700/PHS HHS/ -- P01 AG003991/AG/NIA NIH HHS/ -- P01 AG026276/AG/NIA NIH HHS/ -- P01 AG03991/AG/NIA NIH HHS/ -- P30 NS069329/NS/NINDS NIH HHS/ -- P30-NS069329/NS/NINDS NIH HHS/ -- P50 AG005133/AG/NIA NIH HHS/ -- P50 AG005681/AG/NIA NIH HHS/ -- R01 AG011380/AG/NIA NIH HHS/ -- R01 AG030653/AG/NIA NIH HHS/ -- R01 AG035083/AG/NIA NIH HHS/ -- R01 AG039700/AG/NIA NIH HHS/ -- R01 AG041718/AG/NIA NIH HHS/ -- R01 AG041797/AG/NIA NIH HHS/ -- R01 AG042611/AG/NIA NIH HHS/ -- R01 AG044546/AG/NIA NIH HHS/ -- R01-AG035083/AG/NIA NIH HHS/ -- R01-AG042611/AG/NIA NIH HHS/ -- R01-AG044546/AG/NIA NIH HHS/ -- R01-AG11380/AG/NIA NIH HHS/ -- R01-AG18712/AG/NIA NIH HHS/ -- R01-AG21136/AG/NIA NIH HHS/ -- R01AG21136/AG/NIA NIH HHS/ -- R25 DA027995/DA/NIDA NIH HHS/ -- U24 AG021886/AG/NIA NIH HHS/ -- U24 AG026395/AG/NIA NIH HHS/ -- U24AG21886/AG/NIA NIH HHS/ -- WT089698/Wellcome Trust/United Kingdom -- ZIA AG000950-11/Intramural NIH HHS/ -- ZO1 AG000950-10/AG/NIA NIH HHS/ -- ZO1AG000950-11/AG/NIA NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Jan 23;505(7484):550-4. doi: 10.1038/nature12825. Epub 2013 Dec 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3]. ; 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2]. ; Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [2] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA. ; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. ; Department of Medical and Molecular Genetics, King's College London, 16 De Crespigny Park, London SE5 8AF UK. ; MRC Sudden Death Brain Bank Project, University of Edinburgh, South Bridge, Edinburgh EH8 9YL UK. ; 1] Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK [2] Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia. ; Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, UK. ; Istituto di Genetica delle Popolazioni - CNR, Trav. La Crucca, 3 - Reg. Baldinca - 07100 Li Punti, Sassari, Italy. ; Department of Biology, Brigham Young University, Provo, Utah 84602, USA. ; 1] Department of Mathematics and Statistics, Utah State University, Logan, Utah 84322, USA [2] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA. ; 1] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA [2] Department of Psychology, Utah State University, Logan, Utah 84322, USA. ; 1] Center for Epidemiologic Studies, Utah State University, Logan, Utah 84322, USA [2] Department of Psychology, Utah State University, Logan, Utah 84322, USA [3] Department of Family Consumer and Human Development, Utah State University, Logan, Utah 84322, USA. ; 1] Department of Family Consumer and Human Development, Utah State University, Logan, Utah 84322, USA [2] Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, Utah 84322, USA. ; Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; 1] Alzheimer's Disease Research Center, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [2] Department of Neurology, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; Department of Psychiatry, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK. ; Queen's University Belfast, University Road, Belfast BT7 1NN, UK. ; Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE, UK. ; University of Bonn, Regina-Pacis-Weg 3, 53113 Bonn, Germany. ; University of Bristol, Tyndall Avenue, Bristol, City of Bristol BS8 1TH, UK. ; University of Leeds, Woodhouse Lane, Leeds, West Yorkshire LS2 9JT, UK. ; University of Newcastle, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK. ; University of Manchester, Oxford Road, Manchester, Greater Manchester M13 9PL, UK. ; University of Oxford (OPTIMA), Wellington Square, Oxford OX1 2JD, UK. ; 1] Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Avenida Pio XII, 55. 31008 Pamplona, Navarra, Spain [2] Department of Neurology, Clinica Universidad de Navarra, School of Medicine, University of Navarra Avenida Pio XII, 36. 31008 Pamplona, Spain [3] CIBERNED, Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain. ; Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Avenida Pio XII, 55. 31008 Pamplona, Navarra, Spain. ; University of Washington, 325 Ninth Avenue, Seattle, Washington 98104-2499, USA. ; The Scripps Research Institute, La Jolla, California 3344 North Torrey Pines Court, La Jolla, California 92037, USA. ; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada. ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35 Room 1A1014, 35 Lincoln Drive, Bethesda, Maryland 20892, USA. ; 1] Department of Human Genetics, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [2] Alzheimer's Disease Research Center, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA [3] Department of Neurology, University of Pittsburgh, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA. ; 1] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada [2] Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. ; 1] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Pathology and Immunology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Pathology and Immunology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Department of Neurology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3] Knight ADRC, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA. ; 1] Department of Psychiatry, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [2] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [3] Department of Neurology, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [4] Knight ADRC, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA [5] Department of Genetics, Washington University, 425 South Euclid Avenue, St. Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336208" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wood, Andrew R -- Tuke, Marcus A -- Nalls, Mike A -- Hernandez, Dena G -- Bandinelli, Stefania -- Singleton, Andrew B -- Melzer, David -- Ferrucci, Luigi -- Frayling, Timothy M -- Weedon, Michael N -- G0500070/Medical Research Council/United Kingdom -- England -- Nature. 2014 Oct 2;514(7520):E3-5. doi: 10.1038/nature13691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter EX2 5DW, UK. ; Laboratory of Neurogenetics, National Institute of Aging, Bethesda, Maryland 20892, USA. ; 1] Laboratory of Neurogenetics, National Institute of Aging, Bethesda, Maryland 20892, USA [2] Department of Molecular Neuroscience and Reta Lila Laboratories, Institute of Neurology, UCL, London WC1N IPJ, UK. ; 1] Tuscany Regional Health Agency, Florence, Italy, I.O.T. and Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy [2] Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy. ; Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21225, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25279928" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singleton, Andrew B -- Traynor, Bryan J -- New York, N.Y. -- Science. 2015 Mar 27;347(6229):1422-3. doi: 10.1126/science.aaa9838.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. singleta@mail.nih.gov. ; Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25814571" target="_blank"〉PubMed〈/a〉

Description: Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people 〉60 and 3–4% in people 〉80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs ( P 〈 1 x 10 –16 ) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies ( P 〈 0.001), implicating genes involved in the ‘regulation of leucocyte/lymphocyte activity’ and also ‘cytokine-mediated signalling’ as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.

Description: The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinson's disease and possibly Alzheimer's disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene.