Skip to main content

Missing heritability of complex diseases: case solved?

Human Genetics volume 139, pages 103–113 (2020)Cite this article

Abstract

About 10 years ago, after the first large-scale genome-wide association studies (GWAS) were conducted to find genes associated with common complex diseases, investigators were surprised to find that the amount of heritability explained by the significant hits was very low for almost all the studied traits. Indeed, when compared to heritability estimates expected from the observed trait concordance within families, the heritability explained by the associated variants was always much smaller, more than ten times smaller for some traits. There was thus a problem of “missing heritability” and different hypotheses were proposed to help find this “missing heritability”. These hypotheses involved novel research strategies in which different groups engaged including among others increasing sample sizes of GWAS or looking for rare variants and structural variations that were not captured by the SNP-chips used in GWAS. How successful have these efforts been in finding the “missing heritability”? Could it be that the problem of “missing heritability” was ill-defined? These are the questions that will be addressed in this paper by taking some different examples of complex traits.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  • Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M (2001) Genomewide scans of complex human diseases: true linkage is hard to find. Am J Hum Genet 69:936–950. https://doi.org/10.1086/324069

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Aschard H (2016) A perspective on interaction effects in genetic association studies. Genet Epidemiol 40:678–688. https://doi.org/10.1002/gepi.21989

    Article  PubMed  PubMed Central  Google Scholar 

  • Aschard H, Chen J, Cornelis MC, Chibnik LB, Karlson EW, Kraft P (2012) Inclusion of gene-gene and gene-environment interactions unlikely to dramatically improve risk prediction for complex diseases. Am J Hum Genet 90:962–972. https://doi.org/10.1016/j.ajhg.2012.04.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Auer PL, Lettre G (2015) Rare variant association studies: considerations, challenges and opportunities. Genome Med 7:16. https://doi.org/10.1186/s13073-015-0138-2

    Article  PubMed  PubMed Central  Google Scholar 

  • Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, Collaborators CM (2017) Contribution to Alzheimer’s disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging 59:220e1–220e9. https://doi.org/10.1016/j.neurobiolaging.2017.07.001

    CAS  Article  Google Scholar 

  • Benchek PH, Morris NJ (2013) How meaningful are heritability estimates of liability? Hum Genet 132:1351–1360. https://doi.org/10.1007/s00439-013-1334-z

    Article  PubMed  Google Scholar 

  • Bourrat P, Lu Q, Jablonka E (2017) Why the missing heritability might not be in the DNA. Bioessays. https://doi.org/10.1002/bies.201700067

    Article  PubMed  Google Scholar 

  • Boyle EA, Li YI, Pritchard JK (2017) An expanded view of complex traits: from polygenic to omnigenic. Cell 169:1177–1186. https://doi.org/10.1016/j.cell.2017.05.038

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Browning SR, Browning BL (2011) Population structure can inflate SNP-based heritability estimates. Am J Hum Genet 89:191–193. https://doi.org/10.1016/j.ajhg.2011.05.025(author reply 193-5)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J, Schizophrenia Working Group of the Psychiatric Genomics C, Patterson N, Daly MJ, Price AL, Neale BM (2015) LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet 47:291–295. https://doi.org/10.1038/ng.3211

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Buniello A, MacArthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, McMahon A, Morales J, Mountjoy E, Sollis E, Suveges D, Vrousgou O, Whetzel PL, Amode R, Guillen JA, Riat HS, Trevanion SJ, Hall P, Junkins H, Flicek P, Burdett T, Hindorff LA, Cunningham F, Parkinson H (2019) The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res 47:D1005–D1012. https://doi.org/10.1093/nar/gky1120

    CAS  Article  Google Scholar 

  • Carlborg O, Haley CS (2004) Epistasis: too often neglected in complex trait studies? Nat Rev Genet 5:618–625. https://doi.org/10.1038/nrg1407

    CAS  Article  PubMed  Google Scholar 

  • Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P, Bassett AS, Seller A, Holmes CC, Ragoussis J (2007) QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res 35:2013–2025. https://doi.org/10.1093/nar/gkm076

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Cordell HJ (2002) Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet 11:2463–2468

    CAS  Article  Google Scholar 

  • Cuccaro D, De Marco EV, Cittadella R, Cavallaro S (2017) Copy number variants in Alzheimer’s disease. J Alzheimers Dis 55:37–52. https://doi.org/10.3233/JAD-160469

    CAS  Article  PubMed  Google Scholar 

  • Dandine-Roulland C, Bellenguez C, Debette S, Amouyel P, Genin E, Perdry H (2016) Accuracy of heritability estimations in presence of hidden population stratification. Sci Rep 6:26471. https://doi.org/10.1038/srep26471

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • de Los Campos G, Sorensen D, Gianola D (2015) Genomic heritability: what is it? PLoS Genet 11:e1005048. https://doi.org/10.1371/journal.pgen.1005048

    CAS  Article  PubMed  Google Scholar 

  • Dempfle A, Scherag A, Hein R, Beckmann L, Chang-Claude J, Schafer H (2008) Gene-environment interactions for complex traits: definitions, methodological requirements and challenges. Eur J Hum Genet 16:1164–1172. https://doi.org/10.1038/ejhg.2008.106

    CAS  Article  PubMed  Google Scholar 

  • Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314:989–992. https://doi.org/10.1126/science.1133807

    CAS  Article  PubMed  Google Scholar 

  • Evans LM, Tahmasbi R, Vrieze SI, Abecasis GR, Das S, Gazal S, Bjelland DW, de Candia TR, Haplotype Reference C, Goddard ME, Neale BM, Yang J, Visscher PM, Keller MC (2018) Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits. Nat Genet 50:737–745. https://doi.org/10.1038/s41588-018-0108-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Falconer DS (1965) The inheritance of liability to certain diseases, estimated from the incidence among relatives. Ann Hum Genet 29:51–76

    Article  Google Scholar 

  • Feldman MW, Ramachandran S (2018) Missing compared to what? Revisiting heritability, genes and culture. Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2017.0064

    Article  PubMed  PubMed Central  Google Scholar 

  • Fisher RA (1918) The correlation between relatives on the supposition of Mendelian inheritance. Trans R Soc Edinb Earth Sci 52:399–433

    Article  Google Scholar 

  • Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, Ma C, Fontanillas P, Moutsianas L, McCarthy DJ, Rivas MA, Perry JRB, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Muller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SCJ, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MCY, Palmer ND, Balkau B, Stancakova A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JMM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VKL, Park KS, Saleheen D et al (2016) The genetic architecture of type 2 diabetes. Nature 536:41–47. https://doi.org/10.1038/nature18642

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Gamazon ER, Cox NJ, Davis LK (2014) Structural architecture of SNP effects on complex traits. Am J Hum Genet 95:477–489. https://doi.org/10.1016/j.ajhg.2014.09.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63:168–174. https://doi.org/10.1001/archpsyc.63.2.168

    Article  PubMed  Google Scholar 

  • Gazal S, Loh PR, Finucane HK, Ganna A, Schoech A, Sunyaev S, Price AL (2018) Functional architecture of low-frequency variants highlights strength of negative selection across coding and non-coding annotations. Nat Genet 50:1600–1607. https://doi.org/10.1038/s41588-018-0231-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Genin E, Clerget-Darpoux F (2015a) The missing heritability paradigm: a dramatic resurgence of the GIGO syndrome in genetics. Hum Hered 79:1–4. https://doi.org/10.1159/000370327

    Article  PubMed  Google Scholar 

  • Genin E, Clerget-Darpoux F (2015b) Revisiting the polygenic additive liability model through the example of diabetes mellitus. Hum Hered 80:171–177. https://doi.org/10.1159/000447683

    CAS  Article  PubMed  Google Scholar 

  • Golan D, Lander ES, Rosset S (2014) Measuring missing heritability: inferring the contribution of common variants. Proc Natl Acad Sci USA 111:E5272–E5281. https://doi.org/10.1073/pnas.1419064111

    CAS  Article  PubMed  Google Scholar 

  • Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K (2008) Many sequence variants affecting diversity of adult human height. Nat Genet 40:609–615. https://doi.org/10.1038/ng.122

    CAS  Article  PubMed  Google Scholar 

  • Guo SW, Lange K (2000) Genetic mapping of complex traits: promises, problems, and prospects. Theor Popul Biol 57:1–11. https://doi.org/10.1006/tpbi.2000.1449

    CAS  Article  PubMed  Google Scholar 

  • Haley CS, Visscher PM (1998) Strategies to utilize marker-quantitative trait loci associations. J Dairy Sci 81(Suppl 2):85–97

    CAS  Article  Google Scholar 

  • Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106:9362–9367. https://doi.org/10.1073/pnas.0903103106

    Article  PubMed  Google Scholar 

  • International HapMap C (2005) A haplotype map of the human genome. Nature 437:1299–1320. https://doi.org/10.1038/nature04226

    CAS  Article  Google Scholar 

  • International HapMap C (2002) https://www.genome.gov/10005336/2002-release-genetic-variation-mapping-launch/. Accessed 10 Nov 2018

  • Jun G, Manning A, Almeida M, Zawistowski M, Wood AR, Teslovich TM, Fuchsberger C, Feng S, Cingolani P, Gaulton KJ, Dyer T, Blackwell TW, Chen H, Chines PS, Choi S, Churchhouse C, Fontanillas P, King R, Lee S, Lincoln SE, Trubetskoy V, DePristo M, Fingerlin T, Grossman R, Grundstad J, Heath A, Kim J, Kim YJ, Laramie J, Lee J, Li H, Liu X, Livne O, Locke AE, Maller J, Mazur A, Morris AP, Pollin TI, Ragona D, Reich D, Rivas MA, Scott LJ, Sim X, Tearle RG, Teo YY, Williams AL, Zollner S, Curran JE, Peralta J, Akolkar B, Bell GI, Burtt NP, Cox NJ, Florez JC, Hanis CL, McKeon C, Mohlke KL, Seielstad M, Wilson JG, Atzmon G, Below JE, Dupuis J, Nicolae DL, Lehman D, Park T, Won S, Sladek R, Altshuler D, McCarthy MI, Duggirala R, Boehnke M, Frayling TM, Abecasis GR, Blangero J (2018) Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees. Proc Natl Acad Sci USA 115:379–384. https://doi.org/10.1073/pnas.1705859115

    CAS  Article  PubMed  Google Scholar 

  • Kanoungi G, Nothnagel M (2018) Pathway-induced allelic spectra of diseases in the presence of strong genetic effects. Hum Genet 137:215–230. https://doi.org/10.1007/s00439-018-1872-5

    CAS  Article  PubMed  Google Scholar 

  • Koch L (2014) Epigenetics: an epigenetic twist on the missing heritability of complex traits. Nat Rev Genet 15:218. https://doi.org/10.1038/nrg3698

    CAS  Article  PubMed  Google Scholar 

  • Kryukov GV, Pennacchio LA, Sunyaev SR (2007) Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Hum Genet 80:727–739. https://doi.org/10.1086/513473

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Moron FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fievet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossu P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer’s Disease I, Genetic, Environmental Risk in Alzheimer’s D, Alzheimer’s Disease Genetic C, Cohorts for H, Aging Research in Genomic E, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Lee JJ, Chow CC (2014) Conditions for the validity of SNP-based heritability estimation. Hum Genet 133:1011–1022. https://doi.org/10.1007/s00439-014-1441-5

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee SH, Wray NR, Goddard ME, Visscher PM (2011) Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet 88:294–305. https://doi.org/10.1016/j.ajhg.2011.02.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Diabetes Genetics I, Fusion Kora, Prostate LC, Ovarian Cancer Screening T, Nurses’ Health S, SardiNia Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40:584–591. https://doi.org/10.1038/ng.125

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Lewontin RC (1974) Annotation: the analysis of variance and the analysis of causes. Am J Hum Genet 26:400–411

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lush JL (1937) Animal Breeding Plans. Ames, IA

    Google Scholar 

  • Lynch M, Walsh B (1998) Genetic and the analysis of quantitative traits. Sinauer, Sunderland

    Google Scholar 

  • Mace A, Tuke MA, Deelen P, Kristiansson K, Mattsson H, Noukas M, Sapkota Y, Schick U, Porcu E, Rueger S, McDaid AF, Porteous D, Winkler TW, Salvi E, Shrine N, Liu X, Ang WQ, Zhang W, Feitosa MF, Venturini C, van der Most PJ, Rosengren A, Wood AR, Beaumont RN, Jones SE, Ruth KS, Yaghootkar H, Tyrrell J, Havulinna AS, Boers H, Magi R, Kriebel J, Muller-Nurasyid M, Perola M, Nieminen M, Lokki ML, Kahonen M, Viikari JS, Geller F, Lahti J, Palotie A, Koponen P, Lundqvist A, Rissanen H, Bottinger EP, Afaq S, Wojczynski MK, Lenzini P, Nolte IM, Sparso T, Schupf N, Christensen K, Perls TT, Newman AB, Werge T, Snieder H, Spector TD, Chambers JC, Koskinen S, Melbye M, Raitakari OT, Lehtimaki T, Tobin MD, Wain LV, Sinisalo J, Peters A, Meitinger T, Martin NG, Wray NR, Montgomery GW, Medland SE, Swertz MA, Vartiainen E, Borodulin K, Mannisto S, Murray A, Bochud M, Jacquemont S, Rivadeneira F, Hansen TF, Oldehinkel AJ, Mangino M, Province MA, Deloukas P, Kooner JS, Freathy RM, Pennell C, Feenstra B, Strachan DP, Lettre G, Hirschhorn J, Cusi D, Heid IM, Hayward C, Mannik K, Beckmann JS, Loos RJF, Nyholt DR, Metspalu A, Eriksson JG et al (2017) CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits. Nat Commun 8:744. https://doi.org/10.1038/s41467-017-00556-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Mackay TF, Moore JH (2014) Why epistasis is important for tackling complex human disease genetics. Genome Med 6:124. https://doi.org/10.1186/gm561

    Article  PubMed  Google Scholar 

  • Maher B (2008) Personal genomes: the case of the missing heritability. Nature 456:18–21. https://doi.org/10.1038/456018a

    CAS  Article  Google Scholar 

  • Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753. https://doi.org/10.1038/nature08494

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Marenne G, Chanock SJ, Malats N, Genin E (2013) Advantage of using allele-specific copy numbers when testing for association in regions with common copy number variants. PLoS One 8:e75350. https://doi.org/10.1371/journal.pone.0075350

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C, Highland HM, Rueger S, Thorleifsson G, Justice AE, Lamparter D, Stirrups KE, Turcot V, Young KL, Winkler TW, Esko T, Karaderi T, Locke AE, Masca NG, Ng MC, Mudgal P, Rivas MA, Vedantam S, Mahajan A, Guo X, Abecasis G, Aben KK, Adair LS, Alam DS, Albrecht E, Allin KH, Allison M, Amouyel P, Appel EV, Arveiler D, Asselbergs FW, Auer PL, Balkau B, Banas B, Bang LE, Benn M, Bergmann S, Bielak LF, Bluher M, Boeing H, Boerwinkle E, Boger CA, Bonnycastle LL, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Burt AA, Butterworth AS, Carey DJ, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Galbany JC, Cox AJ, Cuellar-Partida G, Danesh J, Davies G, de Bakker PI, de Borst GJ, de Denus S, de Groot MC, de Mutsert R, Deary IJ, Dedoussis G, Demerath EW, den Hollander AI, Dennis JG, Di Angelantonio E, Drenos F, Du M, Dunning AM, Easton DF, Ebeling T, Edwards TL, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Faul JD et al (2017) Rare and low-frequency coding variants alter human adult height. Nature 542:186–190. https://doi.org/10.1038/nature21039

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • McCarroll SA (2008) Extending genome-wide association studies to copy-number variation. Hum Mol Genet 17:R135–R142. https://doi.org/10.1093/hmg/ddn282

    CAS  Article  PubMed  Google Scholar 

  • Moore DS, Shenk D (2017) The heritability fallacy. Wiley Interdiscip Rev Cogn Sci. https://doi.org/10.1002/wcs.1400

    Article  PubMed  Google Scholar 

  • Nelson RM, Pettersson ME, Carlborg O (2013) A century after Fisher: time for a new paradigm in quantitative genetics. Trends Genet 29:669–676. https://doi.org/10.1016/j.tig.2013.09.006

    CAS  Article  PubMed  Google Scholar 

  • Nicolas G, Charbonnier C, Campion D (2016) From common to rare variants: the genetic component of Alzheimer disease. Hum Hered 81:129–141. https://doi.org/10.1159/000452256

    CAS  Article  PubMed  Google Scholar 

  • Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Sato H, Hori M, Nakamura Y, Tanaka T (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32:650–654. https://doi.org/10.1038/ng1047

    CAS  Article  PubMed  Google Scholar 

  • Reich DE, Lander ES (2001) On the allelic spectrum of human disease. Trends Genet 17:502–510

    CAS  Article  Google Scholar 

  • Ridge PG, Mukherjee S, Crane PK, Kauwe JS, Alzheimer’s Disease Genetics C (2013) Alzheimer’s disease: analyzing the missing heritability. PLoS One 8:e79771. https://doi.org/10.1371/journal.pone.0079771

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517

    CAS  Article  Google Scholar 

  • Ritland K (1996) A marker-based method for inferences about quantitative inheritance in natural populations. Evolution 50:1062–1073. https://doi.org/10.1111/j.1558-5646.1996.tb02347.x

    Article  PubMed  Google Scholar 

  • Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26. https://doi.org/10.1038/ng1718

    CAS  Article  PubMed  Google Scholar 

  • Rovelet-Lecrux A, Legallic S, Wallon D, Flaman JM, Martinaud O, Bombois S, Rollin-Sillaire A, Michon A, Le Ber I, Pariente J, Puel M, Paquet C, Croisile B, Thomas-Anterion C, Vercelletto M, Levy R, Frebourg T, Hannequin D, Campion D, Investigators of the Gp (2012) A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease. Eur J Hum Genet 20:613–617. https://doi.org/10.1038/ejhg.2011.225

    CAS  Article  PubMed  Google Scholar 

  • Saint Pierre A, Genin E (2014) How important are rare variants in common disease? Brief Funct Genom 13:353–361. https://doi.org/10.1093/bfgp/elu025

    Article  Google Scholar 

  • Sandoval-Motta S, Aldana M, Martinez-Romero E, Frank A (2017) the human microbiome and the missing heritability problem. Front Genet 8:80. https://doi.org/10.3389/fgene.2017.00080

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Schork NJ, Murray SS, Frazer KA, Topol EJ (2009) Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev 19:212–219. https://doi.org/10.1016/j.gde.2009.04.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Shen L, Jia J (2016) An overview of genome-wide association studies in Alzheimer’s disease. Neurosci Bull 32:183–190. https://doi.org/10.1007/s12264-016-0011-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Speed D, Hemani G, Johnson MR, Balding DJ (2012) Improved heritability estimation from genome-wide SNPs. Am J Hum Genet 91:1011–1021. https://doi.org/10.1016/j.ajhg.2012.10.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Speed D, Cai N, Consortium U, Johnson MR, Nejentsev S, Balding DJ (2017) Reevaluation of SNP heritability in complex human traits. Nat Genet 49:986–992. https://doi.org/10.1038/ng.3865

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Tenesa A, Haley CS (2013) The heritability of human disease: estimation, uses and abuses. Nat Rev Genet 14:139–149. https://doi.org/10.1038/nrg3377

    CAS  Article  PubMed  Google Scholar 

  • Thomson G (2001) Significance levels in genome scans. Adv Genet 42:475–486

    CAS  Article  Google Scholar 

  • Trerotola M, Relli V, Simeone P, Alberti S (2015) Epigenetic inheritance and the missing heritability. Hum Genom 9:17. https://doi.org/10.1186/s40246-015-0041-3

    CAS  Article  Google Scholar 

  • Visscher PM, Wray NR (2015) Concepts and misconceptions about the polygenic additive model applied to disease. Hum Hered 80:165–170. https://doi.org/10.1159/000446931

    CAS  Article  PubMed  Google Scholar 

  • Visscher PM, Hill WG, Wray NR (2008) Heritability in the genomics era–concepts and misconceptions. Nat Rev Genet 9:255–266. https://doi.org/10.1038/nrg2322

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 17:1665–1674. https://doi.org/10.1101/gr.6861907

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JR, Stevens S, Hall AS, Samani NJ, Shields B, Prokopenko I, Farrall M, Dominiczak A, Diabetes Genetics I, Wellcome Trust Case Control C, Johnson T, Bergmann S, Beckmann JS, Vollenweider P, Waterworth DM, Mooser V, Palmer CN, Morris AD, Ouwehand WH, Cambridge GEMC, Zhao JH, Li S, Loos RJ, Barroso I, Deloukas P, Sandhu MS, Wheeler E, Soranzo N, Inouye M, Wareham NJ, Caulfield M, Munroe PB, Hattersley AT, McCarthy MI, Frayling TM (2008) Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40:575–583. https://doi.org/10.1038/ng.121

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Wellcome Trust Case Control C, Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF, Giannoulatou E, Holmes C, Marchini JL, Stirrups K, Tobin MD, Wain LV, Yau C, Aerts J, Ahmad T, Andrews TD, Arbury H, Attwood A, Auton A, Ball SG, Balmforth AJ, Barrett JC, Barroso I, Barton A, Bennett AJ, Bhaskar S, Blaszczyk K, Bowes J, Brand OJ, Braund PS, Bredin F, Breen G, Brown MJ, Bruce IN, Bull J, Burren OS, Burton J, Byrnes J, Caesar S, Clee CM, Coffey AJ, Connell JM, Cooper JD, Dominiczak AF, Downes K, Drummond HE, Dudakia D, Dunham A, Ebbs B, Eccles D, Edkins S, Edwards C, Elliot A, Emery P, Evans DM, Evans G, Eyre S, Farmer A, Ferrier IN, Feuk L, Fitzgerald T, Flynn E, Forbes A, Forty L, Franklyn JA, Freathy RM, Gibbs P, Gilbert P, Gokumen O, Gordon-Smith K, Gray E, Green E, Groves CJ, Grozeva D, Gwilliam R, Hall A, Hammond N, Hardy M, Harrison P, Hassanali N, Hebaishi H, Hines S, Hinks A, Hitman GA, Hocking L, Howard E, Howard P, Howson JM, Hughes D, Hunt S, Isaacs JD, Jain M, Jewell DP, Johnson T, Jolley JD, Jones IR et al (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464:713–720. https://doi.org/10.1038/nature08979

    CAS  Article  Google Scholar 

  • Wray NR, Wijmenga C, Sullivan PF, Yang J, Visscher PM (2018) Common disease is more complex than implied by the core gene omnigenic model. Cell 173:1573–1580. https://doi.org/10.1016/j.cell.2018.05.051

    CAS  Article  PubMed  Google Scholar 

  • Wright S (1920) The relative importance of heredity and environment in determining the piebald pattern of guinea-pigs. Proc Natl Acad Sci USA 6:320–332

    CAS  Article  Google Scholar 

  • Xue A, Wu Y, Zhu Z, Zhang F, Kemper KE, Zheng Z, Yengo L, Lloyd-Jones LR, Sidorenko J, Wu Y, e QC, McRae AF, Visscher PM, Zeng J, Yang J (2018) Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun 9:2941. https://doi.org/10.1038/s41467-018-04951-w

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, Madden PA, Heath AC, Martin NG, Montgomery GW, Goddard ME, Visscher PM (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42:565–569. https://doi.org/10.1038/ng.608

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88:76–82. https://doi.org/10.1016/j.ajhg.2010.11.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, Frayling TM, Hirschhorn J, Yang J, Visscher PM (2018) Meta-analysis of genome-wide association studies for height and body mass index in ~ 700,000 individuals of European ancestry. bioRxiv. https://doi.org/10.1101/274654

  • Young AI, Frigge ML, Gudbjartsson DF, Thorleifsson G, Bjornsdottir G, Sulem P, Masson G, Thorsteinsdottir U, Stefansson K, Kong A (2018) Relatedness disequilibrium regression estimates heritability without environmental bias. Nat Genet 50:1304–1310. https://doi.org/10.1038/s41588-018-0178-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Zeng J, de Vlaming R, Wu Y, Robinson MR, Lloyd-Jones LR, Yengo L, Yap CX, Xue A, Sidorenko J, McRae AF, Powell JE, Montgomery GW, Metspalu A, Esko T, Gibson G, Wray NR, Visscher PM, Yang J (2018) Signatures of negative selection in the genetic architecture of human complex traits. Nat Genet 50:746–753. https://doi.org/10.1038/s41588-018-0101-4

    CAS  Article  PubMed  Google Scholar 

  • Zhu Z, Bakshi A, Vinkhuyzen AA, Hemani G, Lee SH, Nolte IM, van Vliet-Ostaptchouk JV, Snieder H, LifeLines Cohort S, Esko T, Milani L, Magi R, Metspalu A, Hill WG, Weir BS, Goddard ME, Visscher PM, Yang J (2015) Dominance genetic variation contributes little to the missing heritability for human complex traits. Am J Hum Genet 96:377–385. https://doi.org/10.1016/j.ajhg.2015.01.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Zuk O, Hechter E, Sunyaev SR, Lander ES (2012) The mystery of missing heritability: genetic interactions create phantom heritability. Proc Natl Acad Sci USA 109:1193–1198. https://doi.org/10.1073/pnas.1119675109

    Article  PubMed  Google Scholar 

  • Zuk O, Schaffner SF, Samocha K, Do R, Hechter E, Kathiresan S, Daly MJ, Neale BM, Sunyaev SR, Lander ES (2014) Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci USA 111:E455–E464. https://doi.org/10.1073/pnas.1322563111

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Inserm, Univ Brest, EFS, CHU Brest, UMR 1078, GGB (Génétique, Génomique fonctionnelle et Biotechnologies), Faculté de Médecine, Bâtiment E-IBRBS 2ieme étage, 22 avenue Camille Desmoulins, 29200, Brest Cedex 3, France

    Emmanuelle Génin

Authors
  1. Emmanuelle Génin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emmanuelle Génin.

Ethics declarations

Conflict of interest

The author declares that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Génin, E. Missing heritability of complex diseases: case solved?. Hum Genet 139, 103–113 (2020). https://doi.org/10.1007/s00439-019-02034-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-019-02034-4