Skip to main content
Log in

Atlas of human diseases influenced by genetic variants with extreme allele frequency differences

Human Genetics Aims and scope Submit manuscript

Abstract

Genetic variants with extreme allele frequency differences (EAFD) may underlie some human health disparities across populations. To identify EAFD loci, we systematically analyzed and characterized 81 million genomic variants from 2504 unrelated individuals of 26 world populations (phase III of the 1000 Genomes Project). Our analyses revealed a total of 434 genes, 15 pathways, and 18 diseases and traits influenced by EAFD variants from five continental populations. They included known EAFD genes, such as LCT (lactose tolerance), SLC24A5 (skin pigmentation), and EDAR (hair morphology). We found many novel EAFD genes, including TBC1D2B (autophagy mediator), TRIM40 (gastrointestinal inflammatory regulator), KRT71, KRT75, KRT83, and KRTAP10-1 (hair and epithelial keratin synthesis), PIK3R3 (insulin receptor interaction), DARS (neurological disorders), and NACA2 (skin inflammatory response). Our results also showed four complex diseases significantly associated with EAFD loci, including asthma (adjusted enrichment P = 4 × 10−8), type I diabetes (P = 6 × 10−9), alcohol consumption (P = 0.0002), and attention deficit/hyperactivity disorder (P = 0.003). This study provides a comprehensive atlas of genes, pathways, and human diseases significantly influenced by EAFD variants.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  • 1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526:68–74

    Article  Google Scholar 

  • Arnold M, Soerjomataram I, Ferlay J, Forman D (2015) Global incidence of oesophageal cancer by histological subtype in 2012. Gut 64:381–387

    Article  PubMed  Google Scholar 

  • Baik I, Cho NH, Kim SH, Han BG, Shin C (2011) Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr 93:809–816

    Article  CAS  PubMed  Google Scholar 

  • Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L (2008) Natural selection has driven population differentiation in modern humans. Nat Genet 40:340–345

    Article  CAS  PubMed  Google Scholar 

  • Barrett JH, Iles MM, Harland M, Taylor JC, Aitken JF, Andresen PA, Akslen LA, Armstrong BK, Avril MF, Azizi E, Bakker B, Bergman W, Bianchi-Scarra G, Bressac-de Paillerets B, Calista D, Cannon-Albright LA, Corda E, Cust AE, Debniak T, Duffy D, Dunning AM, Easton DF, Friedman E, Galan P, Ghiorzo P, Giles GG, Hansson J, Hocevar M, Hoiom V, Hopper JL, Ingvar C, Janssen B, Jenkins MA, Jonsson G, Kefford RF, Landi G, Landi MT, Lang J, Lubinski J, Mackie R, Malvehy J, Martin NG, Molven A, Montgomery GW, van Nieuwpoort FA, Novakovic S, Olsson H, Pastorino L, Puig S, Puig-Butille JA, Randerson-Moor J, Snowden H, Tuominen R, Van Belle P, van der Stoep N, Whiteman DC, Zelenika D, Han J, Fang S, Lee JE, Wei Q, Lathrop GM, Gillanders EM, Brown KM, Goldstein AM, Kanetsky PA, Mann GJ, Macgregor S, Elder DE, Amos CI, Hayward NK, Gruis NA, Demenais F, Bishop JA, Bishop DT, Geno MELC (2011) Genome-wide association study identifies three new melanoma susceptibility loci. Nat Genet 43:1108–1113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H Jr, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, McLennan G, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki B, Weinberger SE, Terrin ML, Knatterud GL, Cherniak R, Case Control Etiologic Study of Sarcoidosis research g (2001) Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 164:1885–1889

    Article  CAS  PubMed  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300

    Google Scholar 

  • Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74:1111–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertoni JM, Arlette JP, Fernandez HH, Fitzer-Attas C, Frei K, Hassan MN, Isaacson SH, Lew MF, Molho E, Ondo WG, Phillips TJ, Singer C, Sutton JP, Wolf JE Jr, Ps North American, Melanoma Survey I (2010) Increased melanoma risk in Parkinson disease: a prospective clinicopathological study. Arch Neurol 67:347–352

    Article  PubMed  Google Scholar 

  • Bhatia G, Patterson N, Sankararaman S, Price AL (2013) Estimating and interpreting F ST: the impact of rare variants. Genome Res 23:1514–1521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyle P (2012) Triple-negative breast cancer: epidemiological considerations and recommendations. Ann Oncol 23(Suppl 6):vi7–vi12

    Article  PubMed  Google Scholar 

  • Briscoe VJ, Tate DB, Davis SN (2007) Type 1 diabetes: exercise and hypoglycemia. Appl Physiol Nutr Metab 32:576–582

    Article  CAS  PubMed  Google Scholar 

  • Carrigan MA, Uryasev O, Frye CB, Eckman BL, Myers CR, Hurley TD, Benner SA (2015) Hominids adapted to metabolize ethanol long before human-directed fermentation. Proc Natl Acad Sci USA 112:458–463

    Article  CAS  PubMed  Google Scholar 

  • Castren E, Tanila H (2006) Neurotrophins and dementia—keeping in touch. Neuron 51:1–3

    Article  CAS  PubMed  Google Scholar 

  • Chang ET, Adami HO (2006) The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 15:1765–1777

    Article  CAS  PubMed  Google Scholar 

  • Cooper GM, Stone EA, Asimenos G, Program NCS, Green ED, Batzoglou S, Sidow A (2005) Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15:901–913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Currier RL, Payne DC, Staat MA, Selvarangan R, Shirley SH, Halasa N, Boom JA, Englund JA, Szilagyi PG, Harrison CJ, Klein EJ, Weinberg GA, Wikswo ME, Parashar U, Vinje J, Morrow AL (2015) Innate susceptibility to norovirus infections influenced by FUT2 genotype in a United States pediatric population. Clin Infect Dis 60:1631–1638

    Article  PubMed  PubMed Central  Google Scholar 

  • Dudley JT, Kim Y, Liu L, Markov GJ, Gerold K, Chen R, Butte AJ, Kumar S (2012) Human genomic disease variants: a neutral evolutionary explanation. Genome Res 22:1383–1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ezzati M, Riboli E (2013) Behavioral and dietary risk factors for noncommunicable diseases. N Engl J Med 369:954–964

    Article  CAS  PubMed  Google Scholar 

  • Fraser HB (2013) Gene expression drives local adaptation in humans. Genome Res 23:1089–1096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Barcelo MM, Yeung MY, Miao XP, Tang CS, Cheng G, So MT, Ngan ES, Lui VC, Chen Y, Liu XL, Hui KJ, Li L, Guo WH, Sun XB, Tou JF, Chan KW, Wu XZ, Song YQ, Chan D, Cheung K, Chung PH, Wong KK, Sham PC, Cherny SS, Tam PK (2010) Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2. Hum Mol Genet 19:2917–2925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Genetic Analysis of Psoriasis C, the Wellcome Trust Case Control C, Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, Barton A, Band G, Bellenguez C, Bergboer JG, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Cork MJ, Corvin A, Deloukas P, Dilthey A, Duncanson A, Edkins S, Estivill X, Fitzgerald O, Freeman C, Giardina E, Gray E, Hofer A, Huffmeier U, Hunt SE, Irvine AD, Jankowski J, Kirby B, Langford C, Lascorz J, Leman J, Leslie S, Mallbris L, Markus HS, Mathew CG, McLean WH, McManus R, Mossner R, Moutsianas L, Naluai AT, Nestle FO, Novelli G, Onoufriadis A, Palmer CN, Perricone C, Pirinen M, Plomin R, Potter SC, Pujol RM, Rautanen A, Riveira-Munoz E, Ryan AW, Salmhofer W, Samuelsson L, Sawcer SJ, Schalkwijk J, Smith CH, Stahle M, Su Z, Tazi-Ahnini R, Traupe H, Viswanathan AC, Warren RB, Weger W, Wolk K, Wood N, Worthington J, Young HS, Zeeuwen PL, Hayday A, Burden AD, Griffiths CE, Kere J, Reis A, McVean G, Evans DM, Brown MA, Barker JN, Peltonen L, Donnelly P, Trembath RC (2010) A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 42:985–990

    Article  Google Scholar 

  • Genome of the Netherlands C (2014) Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat Genet 46:818–825

    Article  Google Scholar 

  • Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenwood BM, Bradley AK, Wall RA (1985) Meningococcal disease and season in sub-Saharan Africa. Lancet 2:829–830

    Article  CAS  PubMed  Google Scholar 

  • Gregersen JW, Kranc KR, Ke X, Svendsen P, Madsen LS, Thomsen AR, Cardon LR, Bell JI, Fugger L (2006) Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443:574–577

    CAS  PubMed  Google Scholar 

  • Gronberg H (2003) Prostate cancer epidemiology. Lancet 361:859–864

    Article  PubMed  Google Scholar 

  • Grossman SR, Shlyakhter I, Karlsson EK, Byrne EH, Morales S, Frieden G, Hostetter E, Angelino E, Garber M, Zuk O, Lander ES, Schaffner SF, Sabeti PC (2010) A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327:883–886

    Article  CAS  PubMed  Google Scholar 

  • Grossman SR, Andersen KG, Shlyakhter I, Tabrizi S, Winnicki S, Yen A, Park DJ, Griesemer D, Karlsson EK, Wong SH, Cabili M, Adegbola RA, Bamezai RN, Hill AV, Vannberg FO, Rinn JL, 1000 Genomes Project, Lander ES, Schaffner SF, Sabeti PC (2013) Identifying recent adaptations in large-scale genomic data. Cell 152:703–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grossmann A, Benlasfer N, Birth P, Hegele A, Wachsmuth F, Apelt L, Stelzl U (2015) Phospho-tyrosine dependent protein-protein interaction network. Mol Syst Biol 11:794

    Article  PubMed  Google Scholar 

  • Hamblin MT, Thompson EE, Di Rienzo A (2002) Complex signatures of natural selection at the Duffy blood group locus. Am J Hum Genet 70:369–383

    Article  PubMed  Google Scholar 

  • Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL, Zhao ZZ, Martin NG, Montgomery GW, Hayward NK, Thomas G, Hoover RN, Chanock S, Hunter DJ (2008) A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet 4:e1000074

    Article  PubMed  PubMed Central  Google Scholar 

  • He M, Xu M, Zhang B, Liang J, Chen P, Lee JY, Johnson TA, Li H, Yang X, Dai J, Liang L, Gui L, Qi Q, Huang J, Li Y, Adair LS, Aung T, Cai Q, Cheng CY, Cho MC, Cho YS, Chu M, Cui B, Gao YT, Go MJ, Gu D, Gu W, Guo H, Hao Y, Hong J, Hu Z, Hu Y, Huang J, Hwang JY, Ikram MK, Jin G, Kang DH, Khor CC, Kim BJ, Kim HT, Kubo M, Lee J, Lee J, Lee NR, Li R, Li J, Liu J, Longe J, Lu W, Lu X, Miao X, Okada Y, Ong RT, Qiu G, Seielstad M, Sim X, Song H, Takeuchi F, Tanaka T, Taylor PR, Wang L, Wang W, Wang Y, Wu C, Wu Y, Xiang YB, Yamamoto K, Yang H, Liao M, Yokota M, Young T, Zhang X, Kato N, Wang QK, Zheng W, Hu FB, Lin D, Shen H, Teo YY, Mo Z, Wong TY, Lin X, Mohlke KL, Ning G, Tsunoda T, Han BG, Shu XO, Tai ES, Wu T, Qi L (2015) Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci. Hum Mol Genet 24:1791–1800

    Article  CAS  PubMed  Google Scholar 

  • Heilmann S, Kiefer AK, Fricker N, Drichel D, Hillmer AM, Herold C, Tung JY, Eriksson N, Redler S, Betz RC, Li R, Karason A, Nyholt DR, Song K, Vermeulen SH, Kanoni S, Dedoussis G, Martin NG, Kiemeney LA, Mooser V, Stefansson K, Richards JB, Becker T, Brockschmidt FF, Hinds DA, Nothen MM (2013) Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology. J Invest Dermatol 133:1489–1496

    Article  CAS  PubMed  Google Scholar 

  • Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, Group PSPGS, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Muller U, Schellenberg GD (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705

    Article  PubMed  PubMed Central  Google Scholar 

  • Holsinger KE, Weir BS (2009) Genetics in geographically structured populations: defining, estimating and interpreting F(ST). Nat Rev Genet 10:639–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hradetzky S, Balaji H, Roesner LM, Heratizadeh A, Mittermann I, Valenta R, Werfel T (2013) The human skin-associated autoantigen alpha-NAC activates monocytes and dendritic cells via TLR-2 and primes an IL-12-dependent Th1 response. J Invest Dermatol 133:2289–2292

    Article  CAS  PubMed  Google Scholar 

  • Huson DH, Scornavacca C (2012) Dendroscope 3: an interactive tool for rooted phylogenetic trees and networks. Syst Biol 61:1061–1067

    Article  PubMed  Google Scholar 

  • Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, de Bakker PI (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24:2938–2939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamberov YG, Wang S, Tan J, Gerbault P, Wark A, Tan L, Yang Y, Li S, Tang K, Chen H, Powell A, Itan Y, Fuller D, Lohmueller J, Mao J, Schachar A, Paymer M, Hostetter E, Byrne E, Burnett M, McMahon AP, Thomas MG, Lieberman DE, Jin L, Tabin CJ, Morgan BA, Sabeti PC (2013) Modeling recent human evolution in mice by expression of a selected EDAR variant. Cell 152:691–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M (2014) Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 42:D199–D205

    Article  CAS  PubMed  Google Scholar 

  • Karlsson EK, Kwiatkowski DP, Sabeti PC (2014) Natural selection and infectious disease in human populations. Nat Rev Genet 15:379–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Key FM, Teixeira JC, de Filippo C, Andres AM (2014) Advantageous diversity maintained by balancing selection in humans. Curr Opin Genet Dev 29:45–51

    Article  CAS  PubMed  Google Scholar 

  • Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D, Jones SJ, Marra MA (2009) Circos: an information aesthetic for comparative genomics. Genome Res 19:1639–1645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O’Donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC (2005) SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 310:1782–1786

    Article  CAS  PubMed  Google Scholar 

  • Lao O, Andres AM, Mateu E, Bertranpetit J, Calafell F (2003) Spatial patterns of cystic fibrosis mutation spectra in European populations. Eur J Hum Genet 11:385–394

    Article  CAS  PubMed  Google Scholar 

  • Lee JW, Brancati FL, Yeh HC (2011) Trends in the prevalence of type 2 diabetes in Asians versus whites: results from the United States National Health Interview Survey, 1997–2008. Diabetes Care 34:353–357

    Article  PubMed  PubMed Central  Google Scholar 

  • Li H (2011) Tabix: fast retrieval of sequence features from generic TAB-delimited files. Bioinformatics 27:718–719

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, Middleton L, Berrettini W, Knouff CW, Yuan X, Waeber G, Vollenweider P, Preisig M, Wareham NJ, Zhao JH, Loos RJ, Barroso I, Khaw KT, Grundy S, Barter P, Mahley R, Kesaniemi A, McPherson R, Vincent JB, Strauss J, Kennedy JL, Farmer A, McGuffin P, Day R, Matthews K, Bakke P, Gulsvik A, Lucae S, Ising M, Brueckl T, Horstmann S, Wichmann HE, Rawal R, Dahmen N, Lamina C, Polasek O, Zgaga L, Huffman J, Campbell S, Kooner J, Chambers JC, Burnett MS, Devaney JM, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Epstein S, Wilson JF, Wild SH, Campbell H, Vitart V, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Rader DJ, Franke A, Wittig M, Schafer A, Uda M, Terracciano A, Xiao X, Busonero F, Scheet P, Schlessinger D, St Clair D, Rujescu D, Abecasis GR, Grabe HJ, Teumer A, Volzke H, Petersmann A, John U, Rudan I, Hayward C, Wright AF, Kolcic I, Wright BJ, Thompson JR, Balmforth AJ, Hall AS, Samani NJ, Anderson CA, Ahmad T, Mathew CG, Parkes M, Satsangi J, Caulfield M, Munroe PB, Farrall M, Dominiczak A, Worthington J et al (2010) Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 42:436–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Love-Gregory L, Sherva R, Sun L, Wasson J, Schappe T, Doria A, Rao DC, Hunt SC, Klein S, Neuman RJ, Permutt MA, Abumrad NA (2008) Variants in the CD36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol. Hum Mol Genet 17:1695–1704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madhava V, Burgess C, Drucker E (2002) Epidemiology of chronic hepatitis C virus infection in sub-Saharan Africa. Lancet Infect Dis 2:293–302

    Article  PubMed  Google Scholar 

  • Malnic B, Godfrey PA, Buck LB (2004) The human olfactory receptor gene family. Proc Natl Acad Sci USA 101:2584–2589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCarthy DJ, Humburg P, Kanapin A, Rivas MA, Gaulton K, Cazier JB, Donnelly P (2014) Choice of transcripts and software has a large effect on variant annotation. Genome Med 6(3):26

    Article  PubMed  PubMed Central  Google Scholar 

  • McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, McLaughlin J, Shepherd F, Montpetit A, Narod S, Krokan HE, Skorpen F, Elvestad MB, Vatten L, Njolstad I, Axelsson T, Chen C, Goodman G, Barnett M, Loomis MM, Lubinski J, Matyjasik J, Lener M, Oszutowska D, Field J, Liloglou T, Xinarianos G, Cassidy A, Study E, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, Gonzalez CA, Ramon Quiros J, Martinez C, Navarro C, Ardanaz E, Larranaga N, Kham KT, Key T, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Linseisen J, Boeing H, Hallmans G, Overvad K, Tjonneland A, Kumle M, Riboli E, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) Lung cancer susceptibility locus at 5p15.33. Nat Genet 40:1404–1406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F (2010) Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26:2069–2070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mozaffarian D, Kabagambe EK, Johnson CO, Lemaitre RN, Manichaikul A, Sun Q, Foy M, Wang L, Wiener H, Irvin MR, Rich SS, Wu H, Jensen MK, Chasman DI, Chu AY, Fornage M, Steffen L, King IB, McKnight B, Psaty BM, Djousse L, Chen IY, Wu JH, Siscovick DS, Ridker PM, Tsai MY, Rimm EB, Hu FB, Arnett DK (2015) Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. Am J Clin Nutr 101:398–406

    Article  CAS  PubMed  Google Scholar 

  • Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR, Collaborative Association Study of P (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41:199–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nikolaou V, Stratigos AJ (2014) Emerging trends in the epidemiology of melanoma. Br J Dermatol 170:11–19

    Article  CAS  PubMed  Google Scholar 

  • Noguchi K, Okumura F, Takahashi N, Kataoka A, Kamiyama T, Todo S, Hatakeyama S (2011) TRIM40 promotes neddylation of IKKgamma and is downregulated in gastrointestinal cancers. Carcinogenesis 32:995–1004

    Article  CAS  PubMed  Google Scholar 

  • Ober C, Yao TC (2011) The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 242:10–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ordonez D, Sanchez AJ, Martinez-Rodriguez JE, Cisneros E, Ramil E, Romo N, Moraru M, Munteis E, Lopez-Botet M, Roquer J, Garcia-Merino A, Vilches C (2009) Multiple sclerosis associates with LILRA3 deletion in Spanish patients. Genes Immun 10:579–585

    Article  CAS  PubMed  Google Scholar 

  • Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639–1644

    Article  CAS  PubMed  Google Scholar 

  • Popovic D, Dikic I (2014) TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Rep 15:392–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu C, Kivipelto M, von Strauss E (2009) Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 11:111–128

    PubMed  PubMed Central  Google Scholar 

  • Ralston SH (2013) Clinical practice. Paget’s disease of bone. N Engl J Med 368:644–650

    Article  CAS  PubMed  Google Scholar 

  • Risch N, Tang H, Katzenstein H, Ekstein J (2003) Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection. Am J Hum Genet 72:812–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robert-Gangneux F, Darde ML (2012) Epidemiology of and diagnostic strategies for toxoplasmosis. Clin Microbiol Rev 25:264–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837

    Article  CAS  PubMed  Google Scholar 

  • Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, McCluskey J, Toes RE, La Gruta NL, Purcell AW, Reid HH, Thomas R, Rossjohn J (2013) A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med 210:2569–2582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, Zhai G, Zhao JH, Smith AV, Huffman JE, Albrecht E, Jackson CM, Evans DM, Cadby G, Fornage M, Manichaikul A, Lopez LM, Johnson T, Aldrich MC, Aspelund T, Barroso I, Campbell H, Cassano PA, Couper DJ, Eiriksdottir G, Franceschini N, Garcia M, Gieger C, Gislason GK, Grkovic I, Hammond CJ, Hancock DB, Harris TB, Ramasamy A, Heckbert SR, Heliovaara M, Homuth G, Hysi PG, James AL, Jankovic S, Joubert BR, Karrasch S, Klopp N, Koch B, Kritchevsky SB, Launer LJ, Liu Y, Loehr LR, Lohman K, Loos RJ, Lumley T, Al Balushi KA, Ang WQ, Barr RG, Beilby J, Blakey JD, Boban M, Boraska V, Brisman J, Britton JR, Brusselle GG, Cooper C, Curjuric I, Dahgam S, Deary IJ, Ebrahim S, Eijgelsheim M, Francks C, Gaysina D, Granell R, Gu X, Hankinson JL, Hardy R, Harris SE, Henderson J, Henry A, Hingorani AD, Hofman A, Holt PG, Hui J, Hunter ML, Imboden M, Jameson KA, Kerr SM, Kolcic I, Kronenberg F, Liu JZ, Marchini J, McKeever T, Morris AD, Olin AC, Porteous DJ, Postma DS, Rich SS, Ring SM, Rivadeneira F, Rochat T, Sayer AA, Sayers I, Sly PD et al (2011) Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat Genet 43:1082–1090

    Article  PubMed  Google Scholar 

  • Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, Jakobsdottir M, Steinberg S, Palsson S, Jonasson F, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K (2007) Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 39:1443–1452

    Article  CAS  PubMed  Google Scholar 

  • Taft RJ, Vanderver A, Leventer RJ, Damiani SA, Simons C, Grimmond SM, Miller D, Schmidt J, Lockhart PJ, Pope K, Ru K, Crawford J, Rosser T, de Coo IF, Juneja M, Verma IC, Prabhakar P, Blaser S, Raiman J, Pouwels PJ, Bevova MR, Abbink TE, van der Knaap MS, Wolf NI (2013) Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am J Hum Genet 92:774–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, Manolescu A, Thorleifsson G, Stefansson H, Ingason A, Stacey SN, Bergthorsson JT, Thorlacius S, Gudmundsson J, Jonsson T, Jakobsdottir M, Saemundsdottir J, Olafsdottir O, Gudmundsson LJ, Bjornsdottir G, Kristjansson K, Skuladottir H, Isaksson HJ, Gudbjartsson T, Jones GT, Mueller T, Gottsater A, Flex A, Aben KK, de Vegt F, Mulders PF, Isla D, Vidal MJ, Asin L, Saez B, Murillo L, Blondal T, Kolbeinsson H, Stefansson JG, Hansdottir I, Runarsdottir V, Pola R, Lindblad B, van Rij AM, Dieplinger B, Haltmayer M, Mayordomo JI, Kiemeney LA, Matthiasson SE, Oskarsson H, Tyrfingsson T, Gudbjartsson DF, Gulcher JR, Jonsson S, Thorsteinsdottir U, Kong A, Stefansson K (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452:638–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tishkoff SA, Varkonyi R, Cahinhinan N, Abbes S, Argyropoulos G, Destro-Bisol G, Drousiotou A, Dangerfield B, Lefranc G, Loiselet J, Piro A, Stoneking M, Tagarelli A, Tagarelli G, Touma EH, Williams SM, Clark AG (2001) Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293:455–462

    Article  CAS  PubMed  Google Scholar 

  • Tobacco, Genetics C (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42:441–447

    Article  Google Scholar 

  • Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4:e72

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucl Acids Res 38:e164

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang J, Duncan D, Shi Z, Zhang B (2013) WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucl Acids Res 41:W77–W83

    Article  PubMed  PubMed Central  Google Scholar 

  • Weir BS, Cockerham CC (1984) Estimating F-Statistics for the Analysis of Population-Structure. Evolution 38:1358–1370

    Article  Google Scholar 

  • Weir BS, Hill WG (2002) Estimating F-statistics. Annu Rev Genet 36:721–750

    Article  CAS  PubMed  Google Scholar 

  • Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, Klemm A, Flicek P, Manolio T, Hindorff L, Parkinson H (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucl Acids Res 42:D1001–D1006

    Article  CAS  PubMed  Google Scholar 

  • Wong GK, Yang Z, Passey DA, Kibukawa M, Paddock M, Liu CR, Bolund L, Yu J (2003) A population threshold for functional polymorphisms. Genome Res 13:1873–1879

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau-Chonka DC, Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J, Lo KS, Locke AE, Magi R, Mihailov E, Porcu E, Randall JC, Scherag A, Vinkhuyzen AA, Westra HJ, Winkler TW, Workalemahu T, Zhao JH, Absher D, Albrecht E, Anderson D, Baron J, Beekman M, Demirkan A, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Fraser RM, Goel A, Gong J, Justice AE, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Lui JC, Mangino M, Mateo Leach I, Medina-Gomez C, Nalls MA, Nyholt DR, Palmer CD, Pasko D, Pechlivanis S, Prokopenko I, Ried JS, Ripke S, Shungin D, Stancakova A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet-Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Afzal U, Arnlov J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Bluher M, Bolton JL, Bottcher Y, Boyd HA, Bruinenberg M, Buckley BM, Buyske S, Caspersen IH, Chines PS, Clarke R, Claudi-Boehm S, Cooper M, Daw EW, De Jong PA, Deelen J, Delgado G et al (2014) Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 46:1173–1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng H, Liu T, He W, Li K, Luo R, Nie X, Wu H, Zhao M, Cao H, Zou J, Shan Y, Li S, Yang Q, Asan Ni P, Tian G, Xu J, Liu X, Jiang T, Wu R, Zhou G, Tang M, Qin J, Wang T, Feng S, Li G, Huasang Luosang J, Wang W, Chen F, Wang Y, Zheng X, Li Z, Bianba Z, Yang G, Wang X, Tang S, Gao G, Chen Y, Luo Z, Gusang L, Cao Z, Zhang Q, Ouyang W, Ren X, Liang H, Zheng H, Huang Y, Li J, Bolund L, Kristiansen K, Li Y, Zhang Y, Zhang X, Li R, Li S, Yang H, Nielsen R, Wang J, Wang J (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329:75–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Song F, Liang L, Nan H, Zhang J, Liu H, Wang LE, Wei Q, Lee JE, Amos CI, Kraft P, Qureshi AA, Han J (2013) Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans. Hum Mol Genet 22:2948–2959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Start-up Fund of The University of Vermont to D. Li. The data used in this study were from the 1000 Genomes Project (Phase 3), the KEGG database, the GWAS Catalog (November 13th, 2015), and annotation databases of VEP and ANNOVAR. We would like to thank Dr. Gonçalo Abecasis and Dr. Adam Auton for providing us with the gene-wide PBS statistics information. We are grateful to Dr. Xun Chen and Guangchen Liu for their critical comments and feedback throughout the process of preparing this manuscript. We thank reviewers for their constructive comments.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dawei Li.

Ethics declarations

Conflict of interest

The authors declare no potential conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sulovari, A., Chen, Y.H., Hudziak, J.J. et al. Atlas of human diseases influenced by genetic variants with extreme allele frequency differences. Hum Genet 136, 39–54 (2017). https://doi.org/10.1007/s00439-016-1734-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-016-1734-y

Keywords

Navigation