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2009 © Institute for Molecular Medicine Finland FIMM

Peltonen-Palotie Group

Academician of Science, Professor Leena Peltonen-Palotie, MD, PhD, Research Director, FIMM

Rapidly expanded information of the human genome has facilitated detailed genome-wide analyses of the gensetic risk elements in common diseases, representing common health problems. Professor Leena Peltonen-Palotie's group aims to characterize genetic risk factors in cardiovascular and neuropsychiatric diseases. Utilizing unique study samples of Finland we have, in the collaboration with experts in clinical medicine, epidemiology, statistical genetics and biocomputing, identified a multitude of genetic loci associated with hyperlipidemias, cardiovascular diseases, psychiatric diseases and multiple sclerosis. Several of these loci have also been followed up in terms of their functional, biological and clinical impact. In the case of lactose intolerance, familial combined hyperlipidemia and multiple sclerosis, we have been able to identify DNA variants associated with the disease. Many of the studies involve Finnish epidemiological cohorts and collections of disease families. The research is done in close collaboration with the Wellcome Trust Sanger Institute, Broad Institute and other human genetics laboratories across the world. Also, one of the largest International studies is the ENGAGE integrated project, funded by the Seventh Framework Programme (FP7) of the EU co-ordinated by Peltonen-Palotie and includes many FIMM investigators. Peltonen-Palotie is also coordinator in the Nordic Center of Excellence in Disease Genetics and a co-PI in the Academy of Finland Center of Excellence in Complex Disease Genetrics.

Cardiovascular and metabolic traits

In 2009, FIMM investigators coordinated and/or participated in three major genome-wide screening efforts for lipid genes, which were published in the same issue of Nature genetics (2009, 41). These studies identified a total of 35 loci associated with total cholesterol, HDL, LDL cholesterols and triglycerides and showed their association with coronary heart disease. The work is now being extended in four ways: 1) to a meta-analysis of over 100 000 individuals across the globe with GWAS data, 2) a joint European genome-wide screen of gene-lifestyle interactions, 3) sequencing efforts to finemap causal mutations of the identified regions, and 4) correlating genome-wide marker data with metabolomic and transcriptomic data to screen for functional variation. Also, the clinical impact of the associated loci are currently being studied in a large-scale genotyping effort of Finnish (Finrisk92, 97, 02 and Health2000) and Southern Swedish prospective cohorts with a total of 50 000 individuals followed up 5-23 years.

Schizophrenia and neuropsychiatric disorders

The Peltonen-Palotie group has followed the leads of the DISC1 pathway and monitored the allelic diversity of the pathway genes in the Finnish study sample of over 1000 schizophrenia families. Four out of 12 proteins that bind to the DISC1 protein have demonstrated to carry variants in their genes that are associated with schizophrenia (Tomppo et al, Biol. Psychiatry 2009). Recently, we have found evidence that variants in DISC1 affect measures of psychosis proneness even at the population level (Tomppo et al, Archives of General Psychiatry, 2009).

We are also a partner in the EU SGENE consortium for GWAs on 1433 schizophrenic patients and 33250 controls. This analysis has exposed some interesting loci as well as a novel copy number variation on chromosome 22 (Pietilainen et al, submitted), heavily enriched in the high-risk population on the Eastern boarder of Finland. The major joint scientific achievement in the SGENE consortium was the identification of three rare recurrent microdeletions on 1q21, 15q11.2 and 15q13.3 introducing substantial risk for schizophrenia, published in Nature (2008).

For autism, we have analyzed genome-wide SNP data for affected individuals from 200 Finnish autism spectrum families. This dataset consists of a subset of individuals diagnosed with autistic disorder, and in addition a subset of families with Asperger syndrome (AS). Association analysis, haplotype sharing analysis and CNV analysis have been performed in these datasets (Rehnström et al manuscript in preparation). When genealogical data was used to identify common ancestry of the autism families, two large mega-pedigrees (20 and 9 nuclear families respectively) originating from the Central Finland subisolate were identified. We have used both genome-wide SNP data as well as genome-wide transcript profile data to determine whether these distantly related families share genetic susceptibility factors. In accordance with current results suggesting that autism is caused by rare, de novo mutations which are private to nuclear families, we have not been able to identify shared genetic risk factors in these families. The Finnish ASD dataset has also been included in a large international collaboration headed by Dr. Mark Daly at the Broad Institute, which revealed association between autism and common variants on 5p15 (Weiss et al 2009, Nature). The Finnish autism spectrum disorder dataset has also been included in an international meta-analysis of neuropsychiatric disorders coordinated by Dr Mark Daly at the Broad Institute.

Genetic variation in Finland

We have catalogued Finnish common genetic variance in two studies: first by quantifying the east-west and north-south differences in Finnish genomic architecture using genome-wide association scans together with information of the parental origin of individuals, and second by creating a Finnish Hapmap reference data to comprehensibly describe the Finnish genetic variation. The Finnish Hapmap also allows for precise in silico genotyping of Finnish population-based samples as well as capture of larger structural variants in the Finnish genomes [Surakka et al, submitted]. This reference dataset has been made available to the research community through the Nordic control database and the European Genotyping Archive (EGA).

Selected publications:

Kettunen J, Silander K, Saarela O, Amin N, Müller M, Timpson N, Surakka I, Ripatti S, Laitinen J, Hartikainen AL, Pouta A, Lahermo P, Anttila V, Männistö S, Jula A, Virtamo J, Salomaa V, Lehtimäki T, Raitakari O, Gieger C, Wichmann EH, Van Duijn CM, Smith GD, McCarthy MI, Järvelin MR, Perola M, Peltonen L. European lactase persistence genotype shows evidence of association with increase in body mass index. Hum Mol Genet 2010 Jan 4. [Epub ahead of print]

Tomppo L, Hennah W, Lahermo P, Loukola A, Tuulio-Henriksson A, Suvisaari J, Partonen T, Ekelund J, Lönnqvist J, Peltonen L. Association between genes of Disrupted in schizophrenia 1 (DISC1) interactors and schizophrenia supports the role of the DISC1 pathway in the etiology of major mental illnesses. Biol Psychiatry 2009 Jun 15;65(12):1055-62. Epub 2009 Feb 28.

Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Samani NJ, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Kathiresan S, Meigs JB, Williams G, Nathan DM, MacRae CA, O'Donnell CJ, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Kathiresan S, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Voight BF, Purcell S, Nemesh J, Korn JM, McCarroll SA, Schwartz SM, Yee J, Kathiresan S, Lucas G, Subirana I, Elosua R, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, Samani NJ, Thompson JR, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS; Wellcome Trust Case Control Consortium, Schunkert H, Erdmann J, Linsel-Nitschke P, Lieb W, Ziegler A, König I, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Schunkert H, Samani NJ, Erdmann J, Ouwehand W, Hengstenberg C, Deloukas P, Scholz M, Cambien F, Reilly MP, Li M, Chen Z, Wilensky R, Matthai W, Qasim A, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Epstein SE, Rader DJ, Scheffold T, Berger K, Stoll M, Huge A, Girelli D, Martinelli N, Olivieri O, Corrocher R, Morgan T, Spertus JA, McKeown P, Patterson CC, Schunkert H, Erdmann E, Linsel-Nitschke P, Lieb W, Ziegler A, König IR, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Hólm H, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Engert JC, Do R, Xie C, Anand S, Kathiresan S, Ardissino D, Mannucci PM, Siscovick D, O'Donnell CJ, Samani NJ, Melander O, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Altshuler D. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009 Mar;41(3):334-41. Epub 2009 Feb 8.

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; ENGAGE Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2009 Jan;41(1):47-55. Epub 2008 Dec 7.

Sabatti C, Service SK, Hartikainen AL, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, Sovio U, Ruokonen A, Laitinen J, Jakkula E, Coin L, Hoggart C, Collins A, Turunen H, Gabriel S, Elliot P, McCarthy MI, Daly MJ, Järvelin MR, Freimer NB, Peltonen L. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet. 2009 Jan;41(1):35-46. Epub 2008 Dec 7.