Genome-wide profiling of human diseases

Leena Peltonen led the Genome-wide profiling of human diseases group, aiming to shed light on the complex genetic causes of common diseases. Sadly Leena died on 11 March 2010. [Read obituary]

The Genome-wide profiling of human diseases team is aiming to shed light on the complex genetic causes of common diseases. In particular, the team is focusing on the genetics of cardiovascular and neuropsychiatric diseases.

Data from genome-wide association studies (GWAS) is used for the statistical comparison of large numbers of DNA samples from people suffering from conditions such as heart attacks and hardening of the arteries, as well as neuropsychiatric disorders such as autism, schizophrenia and multiple sclerosis. The team's strategy is to use European population resources, including founder populations such as the Finnish population and the Twins Sample Collections, which both provide invaluable information regarding genetic makeup and disease susceptibility. The team is also coordinating the large European Network of Genomic and Genetic Epidemiology project which aims to characterise genetic and environmental predisposition to cardiovascular and metabolic diseases.

[The Wellcome Trust Sanger Institute]

Background

Our research has its foundation in the possibilities provided by the special population resources of Europe. These include well characterised clinical and epidemiological cohorts and study samples from isolated founder populations, for example, from the National Biobank of Finland. We use the advanced molecular methods of Sanger platforms including genome-wide genotyping of common variants in GWA studies, new sequencing technologies and transcript profiling of relevant cells or tissue biopsies, followed by biocomputational analysis to collect genome-wide information about diseases with complex causes.

Research

Our aims

The Genome-wide profiling of human diseases team aims to translate the wealth of data emerging from large-scale genome-wide analysis in molecular studies in various European populations, into information of direct relevance to future advances in clinical medicine. We currently do this for selected cardiovascular (dyslipidemias, myocardial infarct, atherosclerosis) and neuropsychiatric diseases (autism, schizophrenia multiple sclerosis) through the integration of very large-scale genetic and observable trait (phenotype) data already available from a substantial number of large and well-characterised families and populations.

Our approach

Our research strategy has its foundation in the unique strengths of Europe - well characterised population samples with large amounts of health-related data. Unlike most genome-wide association studies, which have been carried out on patient groups, we have used European population cohorts, not ascertained for any specific trait or disease, and our research has identified more than 20 genes affecting serum lipid levels - the best predictors of cardiovascular disease risk, at the population level. In addition, our first GWA study on a complete birth cohort (1966 Northern Finnish Birth Cohort) demonstrated the value of a founder population in identifying rare variants with high impact on serum lipid levels. From these studies, we hope to identify critical variants and evaluate their potential for assessing cardiovascular risk at the population level.

In cardiovascular diseases, we have contributed to several large international efforts characterising serum lipid traits, myocardial infarct, human height, weight, hypertension and other traits. Such large study samples, with over 100,000 participants, will in future facilitate the analyses of potential sex-specific genes as well as gene-environment interactions. We have also begun functional genomics studies of particular genes, such as those identified in our genomic analyses of monozygotic twins who differ markedly in their levels of obesity. Using this approach we have identified a decrease in mitochondrial copy number in fat tissue of obese twins as well as a potential new obesity gene; encoding factor XIII.

In neuropsychiatric diseases a similar strategy has been adopted resulting in the identification of new MS genes outside the HLA locus and novel copy number variations (CNVs) in families with autism or schizophrenia. Using a ‘reverse genomic’ approach in a birth cohort (starting from the comprehensive GWA-based CNV analyses of the full cohort and proceeding with the identified aberrations to the phenotypes collected during the life time of cohort individuals) we have found that large CNVs are an important contributor to neuronal development and maintenance since carriers of these structural variants have a diversity of CNS disorders.

As well as making advances in the understanding of disease pathogenesis, which may underpin novel therapies, we expect to provide clear proof-of-principle that genetic and genomic discoveries can be translated into diagnostic indicators for other common diseases with the capacity to stratify risk, monitor disease progression and, in future, also predict and monitor therapeutic response.

External links

Selected Publications

  • Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.

    Pajukanta P, Nuotio I, Terwilliger JD, Porkka KV, Ylitalo K, Pihlajamäki J, Suomalainen AJ, Syvänen AC, Lehtimäki T, Viikari JS, Laakso M, Taskinen MR, Ehnholm C and Peltonen L

    Nature genetics 1998;18;4;369-73

    PUBMED: 9537421; DOI: 10.1038/ng0498-369

  • Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

    Paloneva J, Kestilä M, Wu J, Salminen A, Böhling T, Ruotsalainen V, Hakola P, Bakker AB, Phillips JH, Pekkarinen P, Lanier LL, Timonen T and Peltonen L

    Nature genetics 2000;25;3;357-61

    PUBMED: 10888890; DOI: 10.1038/77153

  • Genomics and medicine. Dissecting human disease in the postgenomic era.

    Peltonen L and McKusick VA

    Science (New York, N.Y.) 2001;291;5507;1224-9

    PUBMED: 11233446

  • Classical twin studies and beyond.

    Boomsma D, Busjahn A and Peltonen L

    Nature reviews. Genetics 2002;3;11;872-82

    PUBMED: 12415317; DOI: 10.1038/nrg932

  • Identification of a variant associated with adult-type hypolactasia.

    Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L and Järvelä I

    Nature genetics 2002;30;2;233-7

    PUBMED: 11788828; DOI: 10.1038/ng826

  • Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies.

    Komulainen K, Alanne M, Auro K, Kilpikari R, Pajukanta P, Saarela J, Ellonen P, Salminen K, Kulathinal S, Kuulasmaa K, Silander K, Salomaa V, Perola M and Peltonen L

    PLoS genetics 2006;2;5;e69

    PUBMED: 16699592; DOI: 10.1371/journal.pgen.0020069; PMC: 1458962

  • PRKCA and multiple sclerosis: association in two independent populations.

    Saarela J, Kallio SP, Chen D, Montpetit A, Jokiaho A, Choi E, Asselta R, Bronnikov D, Lincoln MR, Sadovnick AD, Tienari PJ, Koivisto K, Palotie A, Ebers GC, Hudson TJ and Peltonen L

    PLoS genetics 2006;2;3;e42

    PUBMED: 16596167; DOI: 10.1371/journal.pgen.0020042; PMC: 1420678

  • MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome.

    Kyttälä M, Tallila J, Salonen R, Kopra O, Kohlschmidt N, Paavola-Sakki P, Peltonen L and Kestilä M

    Nature genetics 2006;38;2;155-7

    PUBMED: 16415886; DOI: 10.1038/ng1714

  • A common variant of HMGA2 is associated with adult and childhood height in the general population.

    Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JR, Elliott KS, Hackett R, Guiducci C, Shields B, Zeggini E, Lango H, Lyssenko V, Timpson NJ, Burtt NP, Rayner NW, Saxena R, Ardlie K, Tobias JH, Ness AR, Ring SM, Palmer CN, Morris AD, Peltonen L, Salomaa V, Diabetes Genetics Initiative, Wellcome Trust Case Control Consortium, Davey Smith G, Groop LC, Hattersley AT, McCarthy MI, Hirschhorn JN and Frayling TM

    Nature genetics 2007;39;10;1245-50

    PUBMED: 17767157; DOI: 10.1038/ng2121

  • Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.

    Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM and Orho-Melander M

    Nature genetics 2008;40;2;189-97

    PUBMED: 18193044; DOI: 10.1038/ng.75; PMC: 2682493

  • Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.

    Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J, Vuopala K, Ignatius J, Herva R and Peltonen L

    Nature genetics 2008;40;2;155-7

    PUBMED: 18204449; DOI: 10.1038/ng.2007.65; PMC: 2684619

  • Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.

    Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Döring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L and ENGAGE Consortium

    Nature genetics 2009;41;1;47-55

    PUBMED: 19060911; DOI: 10.1038/ng.269; PMC: 2687074