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

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We explored the coding regions of 3,000 Finnish individuals with 3,000 non-Finnish Europeans (NFEs) using whole-exome sequence data, in order to understand how an individual from a bottlenecked population might differ from an individual from an out-bred population. We provide empirical evidence that there are more rare and low-frequency deleterious alleles in Finns compared to NFEs, such that an average Finn has almost twice as many low-frequency complete knockouts of a gene. As such, we hypothesized that some of these low-frequency loss-of-function variants might have important medical consequences in humans and genotyped 83 of these variants in 36,000 Finns. In doing so, we discovered that completely knocking out the TSFM gene might result in inviability or a very severe phenotype in humans and that knocking out the LPA gene might confer protection against coronary heart diseases, suggesting that LPA is likely to be a good potential therapeutic target.

Vyšlo v časopise: Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004494
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004494

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1. PollinTI, DamcottCM, ShenH, OttSH, SheltonJ, et al. (2008) A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322 : 1702–1705.

2. HuygheJR, JacksonAU, FogartyMP, BuchkovichML, StancakovaA, et al. (2012) Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat Genet 45(2): 197–201.

3. StyrkarsdottirU, ThorleifssonG, SulemP, GudbjartssonDF, SigurdssonA, et al. (2013) Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497 : 517–520.

4. JonssonT, AtwalJK, SteinbergS, SnaedalJ, JonssonPV, et al. (2012) A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488 : 96–99.

5. BevilacquaL, DolyS, KaprioJ, YuanQ, TikkanenR, et al. (2010) A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 468 : 1061–1066.

6. GudmundssonJ, SulemP, GudbjartssonDF, MassonG, AgnarssonBA, et al. (2012) A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet 44 : 1326–1329.

7. AminoffM, CarterJE, ChadwickRB, JohnsonC, GrasbeckR, et al. (1999) Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet 21 : 309–313.

8. AaltonenJ, BjorsesP (1999) Cloning of the APECED gene provides new insight into human autoimmunity. Ann Med 31 : 111–116.

9. SavukoskiM, KlockarsT, HolmbergV, SantavuoriP, LanderES, et al. (1998) CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. Nat Genet 19 : 286–288.

10. de la ChapelleA, WrightFA (1998) Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci U S A 95 : 12416–12423.

11. PolviA, LinturiH, VariloT, AnttonenAK, ByrneM, et al. (2013) The Finnish Disease Heritage Database (FinDis) update -⁠ a database for the genes mutated in the Finnish Disease Heritage brought to the next-generation sequencing era. Hum Mutat 34(11): 1458–66.

12. VartiainenE, LaatikainenT, PeltonenM, JuoleviA, MannistoS, et al. (2010) Thirty-five-year trends in cardiovascular risk factors in Finland. Int J Epidemiol 39 : 504–518.

13. RaitakariOT, JuonalaM, RonnemaaT, Keltikangas-JarvinenL, RasanenL, et al. (2008) Cohort profile: the cardiovascular risk in Young Finns Study. Int J Epidemiol 37 : 1220–1226.

14. SmeitinkJA, ElpelegO, AntonickaH, DiepstraH, SaadaA, et al. (2006) Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet 79 : 869–877.

15. VedrenneV, GalmicheL, ChretienD, de LonlayP, MunnichA, et al. (2012) Mutation in the mitochondrial translation elongation factor EFTs results in severe infantile liver failure. J Hepatol 56 : 294–297.

16. AmbergerJ, BocchiniCA, ScottAF, HamoshA (2009) McKusick's Online Mendelian Inheritance in Man (OMIM). Nucleic Acids Res 37: D793–796.

17. MeeteiAR, MedhurstAL, LingC, XueY, SinghTR, et al. (2005) A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet 37 : 958–963.

18. SinghTR, BakkerST, AgarwalS, JansenM, GrassmanE, et al. (2009) Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M. Blood 114 : 174–180.

19. HazraA, KraftP, SelhubJ, GiovannucciEL, ThomasG, et al. (2008) Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet 40 : 1160–1162.

20. LinX, LuD, GaoY, TaoS, YangX, et al. (2012) Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men. Hum Mol Genet 21 : 2610–2617.

21. GrarupN, SulemP, SandholtCH, ThorleifssonG, AhluwaliaTS, et al. (2013) Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet 9: e1003530.

22. ClarkeR, PedenJF, HopewellJC, KyriakouT, GoelA, et al. (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 361 : 2518–2528.

23. KamstrupPR, Tybjaerg-HansenA, SteffensenR, NordestgaardBG (2009) Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301 : 2331–2339.

24. RijkenDC, DirkxSP, LuiderTM, LeebeekFW (2006) Hepatocyte-derived fibrinogen-related protein-1 is associated with the fibrin matrix of a plasma clot. Biochem Biophys Res Commun 350 : 191–194.

25. SmithNL, HuffmanJE, StrachanDP, HuangJ, DehghanA, et al. (2011) Genetic predictors of fibrin D-dimer levels in healthy adults. Circulation 123 : 1864–1872.

26. InouyeM, SilanderK, HamalainenE, SalomaaV, HaraldK, et al. (2010) An immune response network associated with blood lipid levels. PLoS Genet 6: e1001113.

27. InouyeM, KettunenJ, SoininenP, SilanderK, RipattiS, et al. (2010) Metabonomic, transcriptomic, and genomic variation of a population cohort. Mol Syst Biol 6 : 441.

28. LohmuellerKE, IndapAR, SchmidtS, BoykoAR, HernandezRD, et al. (2008) Proportionally more deleterious genetic variation in European than in African populations. Nature 451 : 994–997.

29. SimonsYB, TurchinMC, PritchardJK, SellaG (2014) The deleterious mutation load is insensitive to recent population history. Nat Genet 46 : 220–224.

30. LappalainenT, SammethM, FriedlanderMR, t HoenPA, MonlongJ, et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501(7468): 506–11.

31. MacArthurDG, BalasubramanianS, FrankishA, HuangN, MorrisJ, et al. (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335 : 823–828.

32. ConsortiumG (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45 : 580–585.

33. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 : 2190–2191.