Research Highlights

Utilizing Finnish population cohorts

Genes that we can live without are also interesting drug targets

A multinational team of researchers finished a comprehensive study aiming to identify novel, medically interesting, rare genetic variants. Utilizing Finns they identified several novel gene variants that completely destroy the function of the gene in question. Surprisingly, lacking many of these genes does not cause any health problems and some are even beneficial for the individual. Such genes are very interesting drug targets since the safety of living without them has already been proved by these human “experiments of nature”. Read more.

Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 2014 Jul 31;10(7):e1004494.

Lim ET, Würtz P, Havulinna AS, Palta P, Tukiainen T, Rehnström K, Esko T, Mägi R, Inouye M, Lappalainen T, Chan Y, Salem RM, Lek M, Flannick J, Sim X, Manning A, Ladenvall C, Bumpstead S, Hämäläinen E, Aalto K, Maksimow M, Salmi M,Blankenberg S, Ardissino D, Shah S, Horne B, McPherson R, Hovingh GK, Reilly MP, Watkins H, Goel A, Farrall M, Girelli D, Reiner AP, Stitziel NO, Kathiresan S, Gabriel S, Barrett JC, Lehtimäki T, Laakso M, Groop L, Kaprio J, Perola M, McCarthy MI, Boehnke M, Altshuler DM, Lindgren CM, Hirschhorn JN, Metspalu A, Freimer NB, Zeller T, Jalkanen S, Koskinen S, Raitakari O, Durbin R, MacArthur DG, Salomaa V, Ripatti S, Daly MJ, Palotie A; Sequencing Initiative Suomi (SISu)Project.

Novel blood screen reveals risk of dying among healthy people

Researchers from Finland and Estonia discovered novel biological markers that are strongly indicative of risk of dying from any disease within the near future. Blood samples from over 17,000 generally healthy people were screened for more than a hundred different biomolecules. The team identified four biomarkers that help to identify people at high risk of dying from any disease within the next five years. The measures were independent of well-known risk factors such as age, smoking, drinking, obesity, blood pressure and cholesterol. Read more.

Biomarker profiling by nuclear magnetic resonance spectroscopy for the prediction of all-cause mortality: an observational study of 17,345 persons. PLoS Med. 2014 Feb 25;11(2):e1001606.

Fischer K, Kettunen J, Würtz P, Haller T, Havulinna AS, Kangas AJ, Soininen P,Esko T, Tammesoo ML, Mägi R, Smit S, Palotie A, Ripatti S, Salomaa V, Ala-Korpela M, Perola M, Metspalu A.

Drug sensitivity was modelled and drugs successfully repositioned

Novel therapeutic agent for Tamiflu-resistant pH1N1 influenza virus discovered

FIMM researchers with their collaborators were able to show that the first Tamiflu resistant pandemic influenza pH1N1 viruses have emerged in Finland. Furthermore, they identified a novel antiviral agent MK2206 and showed that the pH1N1 viruses are not able to develop resistance against it. Read more.

Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro. Antimicrob Agents Chemother. 2014 Jul;58(7):3689-96. Epub 2014 Apr 21.

Denisova OV, Söderholm S, Virtanen S, von Schantz C, Bychkov D, Vashchinkina E, Desloovere J, Tynell J, Ikonen N, Theisen LL, Nyman TA, Matikainen S, Kallioniemi O, Julkunen I, Muller CP, Saelens X, Verkhusha VV, Kainov DE.

Drug sensitivity predicted computationally

In this study, researchers at Aalto University and FIMM used genomic changes and other measurements in computational modelling, for predicting drug sensitivity of cancer cells as a function of the cells' molecular properties. The enormous number of variables requires innovative statistical solutions, to be able to computationally use the available genomic information in biomedical research. The publication is based on an international competition of computational drug sensitivity prediction methods in which the research group participated and won it. Read more.

A community effort to assess and improve drug sensitivity prediction algorithms. Nat Biotechnol. 2014 Dec;32(12):1202-12. Epub 2014 Jun 1.

Costello JC, Heiser LM, Georgii E, Gönen M, Menden MP, Wang NJ, Bansal M, Ammad-ud-din M, Hintsanen P, Khan SA, Mpindi JP, Kallioniemi O, Honkela A, Aittokallio T, Wennerberg K; NCI DREAM Community, Collins JJ, Gallahan D, Singer D, Saez-Rodriguez J, Kaski S, Gray JW, Stolovitzky G.

Novel diagnostics developed

A novel “Man and Machine” decision support system makes malaria diagnostics more effective

A research group led by FIMM’s Research Director Johan Lundin developed a novel “man and machine” decision support system for diagnosing malaria infection. The method is based on computer vision algorithms similar to those used in facial recognition systems combined with visualization of only the diagnostically most relevant areas. Tablet computers can be utilized in viewing the images. Read more.

A malaria diagnostic tool based on computer vision screening and visualization of Plasmodium falciparum candidate areas in digitized blood smears. PLoS One. 2014 Aug 21;9(8):e104855.

Linder N, Turkki R, Walliander M, Mårtensson A, Diwan V, Rahtu E, Pietikäinen M, Lundin M, Lundin J.

High impact variants, novel mutations and causative genes

A new genetic cause for a progressive form of epilepsy identified

In this work, an international research consortium discovered a new gene underlying progressive myoclonus epilepsy, one of the most devastating forms of epilepsy. The study showed that a single mutation in a potassium ion channel gene KCNC1 underlies a substantial proportion of unsolved cases. The researchers estimated that the mutation is carried by hundreds of patients worldwide. Read more.

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015 Jan;47(1):39-46. Epub 2014 Nov 17.

Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand MS, Andermann E, Andermann F, Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, Ahmad J, Ahmad A, Baykan B, Said E, Topcu M, Riguzzi P, King MD, Ozkara C, Andrade DM, Engelsen BA, Crespel A, Lindenau M, Lohmann E, Saletti V, Massano J, Privitera M, Espay AJ, Kauffmann B, Duchowny M, Møller RS, Straussberg R, Afawi Z, Ben-Zeev B, Samocha KE, Daly MJ, Petrou S, Lerche H, Palotie A, Lehesjoki AE.

Novel mutations identified in STAT5B gene as a possible cause of acute lymphoblastic leukaemia

The FIMM personalised medicine team and their clinical collaborators recently discovered mutations to STAT5B and their functional significance in large granular lymphocytic leukaemia. In this study, the researchers were able to show that mutations to STAT5B are also recurrent in T-cell acute lymphoblastic leukaemia. Before this, activating mutations in STAT5B had not been described in other cancer types.

Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia. Leukemia. 2014 Aug;28(8):1738-42. Epub 2014 Feb 27.

Kontro M, Kuusanmäki H, Eldfors S, Burmeister T, Andersson EI, Bruserud O, Brümmendorf TH, Edgren H, Gjertsen BT, Itälä-Remes M, Lagström S, Lohi O, Lundán T, Martí JM, Majumder MM, Parsons A, Pemovska T, Rajala H, Vettenranta K, Kallioniemi O, Mustjoki S, Porkka K, Heckman CA.

Novel sodium channel mutation identified in a Finnish family – a new piece in the puzzle of genetic cardiac arrhythmias

In this study, the cause of a disease called exercise-induced polymorphic ventricular arrhythmia was found in a large Finnish family. Samples from eight affected family members were exome sequenced at the FIMM Technology Centre. Based on these results, the disease causing mutation was revealed. The cause of the symptoms was shown to be a novel missense mutation in one of the known arrhythmia genes, SCN5A. Read more.

Gain-of-function mutation of the SCN5A gene causes exercise-induced polymorphic ventricular arrhythmias. Circulation: Cardiovascular Genetics 2014 Dec;7(6):771-81. Epub 2014 Sep 10.

Swan H, Amarouch MY, Leinonen J, Marjamaa A, Kucera JP, Laitinen-Forsblom PJ, Lahtinen AM, Palotie A, Kontula K, Toivonen L, Abriel H, Widén E.

Large GWAS studies and beyond

Opening “the X-files” helped researchers to understand why women and men differ in height

In this study, FIMM researchers identified novel X-chromosomal genetic variants that influence human height. The team analysed thoroughly the commonly occurring genetic variation in chromosome X in almost 25,000 Northern European individuals with diverse health-related information available. The study showed that a genetic variant close to ITM2A, a gene that has a role in cartilage development, is frequent among the people being shorter than average. The identified variant was also shown to increase the expression of ITM2A, suggesting that the more the gene is expressed, the shorter the person will be. Interestingly, the effect of this variant on height was shown to be much stronger in women. Read more.

Chromosome X-wide association study identifies Loci for fasting insulin and height and evidence for incomplete dosage compensation. PLoS Genet. 2014 Feb 6;10(2):e1004127.

Tukiainen T, Pirinen M, Sarin AP, Ladenvall C, Kettunen J, Lehtimäki T, Lokki ML, Perola M, Sinisalo J, Vlachopoulou E, Eriksson JG, Groop L, Jula A, Järvelin MR, Raitakari OT, Salomaa V, Ripatti S.

New light on biology underlying schizophrenia

As part of a multinational, collaborative effort, FIMM researchers helped identify over 100 locations in the human genome associated with the risk of developing schizophrenia in what is the largest genomic study published on any psychiatric disorder to date. The findings, which were published in Nature, point to biological mechanisms and pathways that may underlie schizophrenia, and could lead to new approaches to treating the disorder. Read more.

Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014 Jul 24;511(7510):421-7. Epub 2014 Jul 22.

Schizophrenia Working Group of the Psychiatric Genomics Consortium.

Genetic loci for body mass and menarche are important in male puberty

In this study, the researchers performed genome-wide association meta-analysis in over 11,000 European samples with data on early pubertal traits. The group reported the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) gene. They were also able to show that some menarche loci are important for pubertal initiation in both sexes.

Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. Human Molecular Genetics 2014 Aug 15;23(16):4452-64. Epub 2014 Apr 25.

Cousminer DL, Stergiakouli E, Berry DJ, Ang W, Groen-Blokhuis MM, Körner A, Siitonen N, Ntalla I, Marinelli M, Perry JR, Kettunen J, Jansen R, Surakka I, Timpson NJ, Ring S, Mcmahon G, Power C, Wang C, Kähönen M, Viikari J, Lehtimäki T, Middeldorp CM, Hulshoff Pol HE, Neef M, Weise S, Pahkala K, Niinikoski H, Zeggini E, Panoutsopoulou K, Bustamante M, Penninx BW; ReproGen Consortium, Murabito J, Torrent M, Dedoussis GV, Kiess W, Boomsma DI, Pennell CE, Raitakari OT, Hyppönen E, Davey Smith G, Ripatti S, McCarthy MI, Widén E; Early Growth Genetics Consortium.

Research Highlights