Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population

被引：300

作者：

Lim, Elaine T. ^{[1
,2
,3
,4
]}

Wuertz, Peter ^{[5
,6
,7
]}

Havulinna, Aki S. ^{[6
]}

Palta, Priit ^{[5
,8
]}

Tukiainen, Taru ^{[1
,2
,3
]}

Rehnstrom, Karola ^{[8
]}

Esko, Tonu ^{[2
,3
,9
,10
,11
,12
]}

Magi, Reedik ^{[9
]}

Inouye, Michael ^{[13
,14
]}

Lappalainen, Tuuli ^{[15
,16
]}

Chan, Yingleong ^{[2
,4
,10
,11
,12
]}

Salem, Rany M. ^{[2
,10
,11
,12
]}

Lek, Monkol ^{[1
,2
,3
]}

Flannick, Jason ^{[2
,3
]}

Sim, Xueling ^{[17
,18
]}

Manning, Alisa ^{[2
]}

Ladenvall, Claes ^{[5
,19
]}

Bumpstead, Suzannah ^{[8
]}

Hamalainen, Eija

Aalto, Kristiina ^{[20
]}

Maksimow, Mikael ^{[20
]}

Salmi, Marko ^{[21
,22
]}

Blankenberg, Stefan ^{[23
,24
]}

Ardissino, Diego ^{[25
]}

Shah, Svati ^{[26
]}

Horne, Benjamin ^{[27
]}

McPherson, Ruth ^{[28
]}

Hovingh, Gerald K. ^{[29
]}

Reilly, Muredach P. ^{[30
]}

Watkins, Hugh ^{[31
]}

Goel, Anuj ^{[31
]}

Farrall, Martin ^{[31
]}

Girelli, Domenico ^{[32
]}

Reiner, Alex P. ^{[33
]}

Stitziel, Nathan O. ^{[34
]}

Kathiresan, Sekar ^{[35
]}

Gabriel, Stacey ^{[2
]}

Barrett, Jeffrey C. ^{[8
]}

Lehtimaki, Terho ^{[36
]}

Laakso, Markku

Groop, Leif ^{[5
,19
]}

Kaprio, Jaakko ^{[5
,37
,38
]}

Perola, Markus ^{[5
]}

McCarthy, Mark I. ^{[39
,40
,41
]}

Boehnke, Michael ^{[17
,18
]}

Altshuler, David M. ^{[2
,3
]}

Lindgren, Cecilia M. ^{[1
,2
,42
]}

Hirschhorn, Joel N. ^{[2
,10
,11
,12
]}

Metspalu, Andres ^{[9
]}

Freimer, Nelson B. ^{[43
]}

机构：

[1] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[3] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[4] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA USA

[5] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[6] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[7] Univ Oulu, Inst Hlth Sci, Oulu, Finland

[8] Wellcome Trust Sanger Inst, Cambridge, England

[9] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[10] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA

[11] Childrens Hosp Boston, Div Genet, Boston, MA USA

[12] Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA USA

[13] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia

[14] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia

[15] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[16] Stanford Ctr Computat Evolutionary & Human Gen, Stanford, CA USA

[17] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[18] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[19] Lund Univ, Skane Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden

[20] Univ Turku, MediCity, Turku, Finland

[21] Univ Turku, Dept Med Microbiol & Immunol, Turku, Finland

[22] Natl Inst Hlth & Welf, Turku, Finland

[23] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany

[24] DZHK German Ctr Cardiovasc Res, Hamburg, Germany

[25] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy

[26] Duke Univ Med Ctr, Dept Med, Durham, NC USA

[27] Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA

[28] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada

[29] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands

[30] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA

[31] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England

[32] Univ Verona, Sch Med, Dept Med, I-37100 Verona, Italy

[33] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[34] Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA

[35] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[36] Univ Tampere, Sch Med, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland

[37] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland

[38] Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, Helsinki, Finland

[39] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[40] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[41] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England

[42] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[43] Univ Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA

[44] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Helsinki, Finland

[45] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland

[46] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland

[47] Univ Helsinki, Hjelt Inst, Dept Biometry, Helsinki, Finland

[48] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

来源：

PLOS GENETICS | 2014年 / 10卷 / 07期

基金：

英国惠康基金; 英国医学研究理事会; 芬兰科学院;

关键词：

CARDIOVASCULAR RISK; MUTATION; GENE; ASSOCIATION; DISEASE; PROFILE; LEVEL;

D O I：

10.1371/journal.pgen.1004494

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p < 5 x 10(-8)) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5 x 10(-117)). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3 x 10(-4)), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.

引用

页数：12

共 33 条

[1]

Aaltonen J, 1999, ANN MED, V31, P111, DOI 10.3109/07853899708998786

[2] McKusick's Online Mendelian Inheritance in Man (OMIM®) [J].

Amberger, Joanna ;

Bocchini, Carol A. ;

Scott, Alan F. ;

Hamosh, Ada .

NUCLEIC ACIDS RESEARCH, 2009, 37 :D793-D796

[3] Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1 [J].

Aminoff, M ;

Carter, JE ;

Chadwick, RB ;

Johnson, C ;

Gräsbeck, R ;

Abdelaal, MA ;

Broch, H ;

Jenner, LB ;

Verroust, PJ ;

Moestrup, SK ;

de la Chapelle, A ;

Krahe, R .

NATURE GENETICS, 1999, 21 (03) :309-313

[4] A population-specific HTR2B stop codon predisposes to severe impulsivity [J].

Bevilacqua, Laura ;

Doly, Stephane ;

Kaprio, Jaakko ;

Yuan, Qiaoping ;

Tikkanen, Roope ;

Paunio, Tiina ;

Zhou, Zhifeng ;

Wedenoja, Juho ;

Maroteaux, Luc ;

Diaz, Silvina ;

Belmer, Arnaud ;

Hodgkinson, Colin A. ;

Dell'Osso, Liliana ;

Suvisaari, Jaana ;

Coccaro, Emil ;

Rose, Richard J. ;

Peltonen, Leena ;

Virkkunen, Matti ;

Goldman, David .

NATURE, 2010, 468 (7327) :1061-U460

[5] Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease [J].

Clarke, Robert ;

Peden, John F. ;

Hopewell, Jemma C. ;

Kyriakou, Theodosios ;

Goel, Anuj ;

Heath, Simon C. ;

Parish, Sarah ;

Barlera, Simona ;

Franzosi, Maria Grazia ;

Rust, Stephan ;

Bennett, Derrick ;

Silveira, Angela ;

Malarstig, Anders ;

Green, Fiona R. ;

Lathrop, Mark ;

Gigante, Bruna ;

Leander, Karin ;

de Faire, Ulf ;

Seedorf, Udo ;

Hamsten, Anders ;

Collins, Rory ;

Watkins, Hugh ;

Farrall, Martin .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (26) :2518-2528

[6] Linkage disequilibrium mapping in isolated populations: The example of Finland revisited [J].

De La Chapelle, A ;

Wright, FA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12416-12423

[7] Genetic Architecture of Vitamin B12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets [J].

Grarup, Niels ;

Sulem, Patrick ;

Sandholt, Camilla H. ;

Thorleifsson, Gudmar ;

Ahluwalia, Tarunveer S. ;

Steinthorsdottir, Valgerdur ;

Bjarnason, Helgi ;

Gudbjartsson, Daniel F. ;

Magnusson, Olafur T. ;

Sparso, Thomas ;

Albrechtsen, Anders ;

Kong, Augustine ;

Masson, Gisli ;

Tian, Geng ;

Cao, Hongzhi ;

Nie, Chao ;

Kristiansen, Karsten ;

Husemoen, Lise Lotte ;

Thuesen, Betina ;

Li, Yingrui ;

Nielsen, Rasmus ;

Linneberg, Allan ;

Olafsson, Isleifur ;

Eyjolfsson, Gudmundur I. ;

Jorgensen, Torben ;

Wang, Jun ;

Hansen, Torben ;

Thorsteinsdottir, Unnur ;

Stefansson, Kari ;

Pedersen, Oluf .

PLOS GENETICS, 2013, 9 (06)

[8] A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer [J].

Gudmundsson, Julius ;

Sulem, Patrick ;

Gudbjartsson, Daniel F. ;

Masson, Gisli ;

Agnarsson, Bjarni A. ;

Benediktsdottir, Kristrun R. ;

Sigurdsson, Asgeir ;

Magnusson, Olafur Th ;

Gudjonsson, Sigurjon A. ;

Magnusdottir, Droplaug N. ;

Johannsdottir, Hrefna ;

Helgadottir, Hafdis Th ;

Stacey, Simon N. ;

Jonasdottir, Adalbjorg ;

Olafsdottir, Stefania B. ;

Thorleifsson, Gudmar ;

Jonasson, Jon G. ;

Tryggvadottir, Laufey ;

Navarrete, Sebastian ;

Fuertes, Fernando ;

Helfand, Brian T. ;

Hu, Qiaoyan ;

Csiki, Irma E. ;

Mates, Ioan N. ;

Jinga, Viorel ;

Aben, Katja K. H. ;

van Oort, Inge M. ;

Vermeulen, Sita H. ;

Donovan, Jenny L. ;

Hamdy, Freddy C. ;

Ng, Chi-Fai ;

Chiu, Peter K. F. ;

Lau, Kin-Mang ;

Ng, Maggie C. Y. ;

Gulcher, Jeffrey R. ;

Kong, Augustine ;

Catalona, William J. ;

Mayordomo, Jose I. ;

Einarsson, Gudmundur V. ;

Barkardottir, Rosa B. ;

Jonsson, Eirikur ;

Mates, Dana ;

Neal, David E. ;

Kiemeney, Lambertus A. ;

Thorsteinsdottir, Unnur ;

Rafnar, Thorunn ;

Stefansson, Kari .

NATURE GENETICS, 2012, 44 (12) :1326-1329

[9] Common variants of FUT2 are associated with plasma vitamin B12 levels [J].

Hazra, Aditi ;

Kraft, Peter ;

Selhub, Jacob ;

Giovannucci, Edward L. ;

Thomas, Gilles ;

Hoover, Robert N. ;

Chanock, Stephen J. ;

Hunter, David J. .

NATURE GENETICS, 2008, 40 (10) :1160-1162

[10] Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion [J].

Huyghe, Jeroen R. ;

Jackson, Anne U. ;

Fogarty, Marie P. ;

Buchkovich, Martin L. ;

Stancakova, Alena ;

Stringham, Heather M. ;

Sim, Xueling ;

Yang, Lingyao ;

Fuchsberger, Christian ;

Cederberg, Henna ;

Chines, Peter S. ;

Teslovich, Tanya M. ;

Romm, Jane M. ;

Ling, Hua ;

McMullen, Ivy ;

Ingersoll, Roxann ;

Pugh, Elizabeth W. ;

Doheny, Kimberly F. ;

Neale, Benjamin M. ;

Daly, Mark J. ;

Kuusisto, Johanna ;

Scott, Laura J. ;

Kang, Hyun Min ;

Collins, Francis S. ;

Abecasis, Goncalo R. ;

Watanabe, Richard M. ;

Boehnke, Michael ;

Laakso, Markku ;

Mohlke, Karen L. .

NATURE GENETICS, 2013, 45 (02) :197-201

← 1 2 3 4 →