No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

PLoS Genetics

Volumn 12, Issue 10, 2016, Pages

  Johnson, Emma C ^a   Bjelland, Douglas W ^a   Howrigan, Daniel P ^b,c   Abdellaoui, Abdel ^d   Breen, Gerome ^e   Børglum, Anders ^f,g,h,aa   Cichon, Sven ^i,j,k,aa   Degenhardt, Franziska ^i,aa   Forstner, Andreas J ⁱ   Frank, Josef ^l,aa   Genovese, Giulio ^c,aa   Heilmann Heimbach, Stefanie ⁱ   Herms, Stefan ^i,j,aa   Hoffman, Per ^i,j   Maier, Wolfgang ^i,aa   Mattheisen, Manuel ^i,aa   Morris, Derek W ^aa   Mowry, Bryan ^n,o   Müller Mhysok, Betram ^p,q,r   Neale, Benjamin ^b,c   Nenadic, Igor ^s,aa   Nöthen, Markus M ^i,aa   O’Dushlaine, Colm ^t   Rietschel, Marcella ^l,aa   Ruderfer, Douglas M ^u,aa   Rujescu, Dan ^v,w,aa   Schulze, Thomas G ^v,aa   Simonson, Matthew A ^x   Stahl, Eli ^c,u   Strohmaier, Jana ^l,aa   Witt, Stephanie H ^l,aa   Ripke, Stephan ^aa   Neale, Benjamin M ^aa   Corvin, Aiden ^aa   Walters, James T R ^aa   Farh, Kai How ^aa   Holmans, Peter A ^aa   Lee, Phil ^aa   Bulik Sullivan, Brendan ^aa   Collier, David A ^aa   Huang, Hailiang ^aa   Pers, Tune H ^aa   Agartz, Ingrid ^aa   Agerbo, Esben ^aa   Albus, Margot ^aa   Alexander, Madeline ^aa   Amin, Farooq ^aa   Bacanu, Silviu A ^aa   Begemann, Martin ^aa   Belliveau, Richard A ^aa   Bene, Judit ^aa   Bergen, Sarah E ^aa   Bevilacqua, Elizabeth ^aa   Bigdeli, Tim B ^aa   Black, Donald W ^aa   Bruggeman, Richard ^aa   Buccola, Nancy G ^aa   Buckner, Randy L ^aa   Byerley, William ^aa   Cahn, Wiepke ^aa   Cai, Guiqing ^aa   Campion, Dominique ^aa   Cantor, Rita M ^aa   Carr, Vaughan J ^aa   Carrera, Noa ^aa   Catts, Stanley V ^aa   Chambert, Kimberly D ^aa   Chan, Raymond C K ^aa   Chen, Ronald Y L ^aa   Chen, Eric Y H ^aa   Cheng, Wei ^aa   Cheung, Eric F C ^aa   Chong, Siow Ann ^aa   Robert Cloninger, C ^aa   Cohen, David ^aa   Cohen, Nadine ^aa   Cormican, Paul ^aa   Craddock, Nick ^aa   Crowley, James J ^aa   Curtis, David ^aa   Davidson, Michael ^aa   Davis, Kenneth L ^aa   Del Favero, Jurgen ^aa   Demontis, Ditte ^aa   Dikeos, Dimitris ^aa   Dinan, Timothy ^aa   Djurovic, Srdjan ^aa   Donohoe, Gary ^aa   Drapeau, Elodie ^aa   Duan, Jubao ^aa   Dudbridge, Frank ^aa   Durmishi, Naser ^aa   Eichhammer, Peter ^aa   Eriksson, Johan ^aa   Escott Price, Valentina ^aa   Essioux, Laurent ^aa   Fanous, Ayman H ^aa   Farrell, Martilias S ^aa   Franke, Lude ^aa   Freedman, Robert ^aa   Freimer, Nelson B ^aa   Friedl, Marion ^aa   Friedman, Joseph I ^aa   Fromer, Menachem ^aa   Georgieva, Lyudmila ^aa   Giegling, Ina ^aa   Giusti Rodríguez, Paola ^aa   Godard, Stephanie ^aa   Goldstein, Jacqueline I ^aa   Golimbet, Vera ^aa   Gopal, Srihari ^aa   Gratten, Jacob ^aa   de Haan, Lieuwe ^aa   Hammer, Christian ^aa   Hamshere, Marian L ^aa   Hansen, Mark ^aa   Hansen, Thomas ^aa   Haroutunian, Vahram ^aa   Hartmann, Annette M ^aa   Henskens, Frans A ^aa   Hirschhorn, Joel N ^aa   Hoffmann, Per ^aa   Hofman, Andrea ^aa   Hollegaard, Mads V ^aa   Hougaard, David M ^aa   Ikeda, Masashi ^aa   Joa, Inge ^aa   Julià, Antonio ^aa   Kahn, René S ^aa   Kalaydjieva, Luba ^aa   Karachanak Yankova, Sena ^aa   Karjalainen, Juha ^aa   Kavanagh, David ^aa   Kennedy, James L ^aa   Khrunin, Andrey ^aa   Kim, Yunjung ^aa   Klovins, Janis ^aa   Knowles, James A ^aa   Konte, Bettina ^aa   Kucinskas, Vaidutis ^aa   Kucinskiene, Zita Ausrele ^aa   Kuzelova Ptackova, Hana ^aa   Kähler, Anna K ^aa   Laurent, Claudine ^aa   Chee Keong, Jimmy Lee ^aa   Hong Lee, S ^aa   Legge, Sophie E ^aa   Lerer, Bernard ^aa   Li, Miaoxin ^aa   Li, Tao ^aa   Liang, Kung Yee ^aa   Lieberman, Jeffrey ^aa   Limborska, Svetlana ^aa   Loughland, Carmel M ^aa   Lubinski, Jan ^aa   Lönnqvist, Jouko ^aa   Macek, Milan ^aa   Magnusson, Patrik K E ^aa   Maher, Brion S ^aa   Mallet, Jacques ^aa   Marsal, Sara ^aa   Mattingsdal, Morten ^aa   McCarley, Robert W ^aa   McDonald, Colm ^aa   McIntosh, Andrew M ^aa   Meier, Sandra ^aa   Meijer, Carin J ^aa   Melegh, Bela ^aa   Melle, Ingrid ^aa   Mesholam Gately, Raquelle I ^aa   Metspalu, Andres ^aa   Michie, Patricia T ^aa   Milani, Lili ^aa   Milanova, Vihra ^aa   Mokrab, Younes ^aa   Mors, Ole ^aa   Murphy, Kieran C ^aa   Murray, Robin M ^aa   Myin Germeys, Inez ^aa   Müller Myhsok, Bertram ^aa   Nelis, Mari ^aa   Nertney, Deborah A ^aa   Nestadt, Gerald ^aa   Nicodemus, Kristin K ^aa   Nikitina Zake, Liene ^aa   Nisenbaum, Laura ^aa   Nordin, Annelie ^aa   O'Callaghan, Eadbhard ^aa   O'Dushlaine, Colm ^aa   Anthony O'Neill, F ^aa   Oh, Sang Yun ^aa   Olincy, Ann ^aa   Olsen, Line ^aa   Van Os, Jim ^aa   Pantelis, Christos ^aa   Papadimitriou, George N ^aa   Papiol, Sergi ^aa   Parkhomenko, Elena ^aa   Pato, Michele T ^aa   Paunio, Tiina ^aa   Pejovic Milovancevic, Milica ^aa   Perkins, Diana O ^aa   Pietiläinen, Olli ^aa   Pimm, Jonathan ^aa   Pocklington, Andrew J ^aa   Powell, John ^aa   Price, Alkes ^aa   Pulver, Ann E ^aa   Purcell, Shaun M ^aa   Quested, Digby ^aa   Rasmussen, Henrik B ^aa   Reichenberg, Abraham ^aa   Reimers, Mark A ^aa   Richards, Alexander L ^aa   Roffman, Joshua L ^aa   Roussos, Panos ^aa   Salomaa, Veikko ^aa   Sanders, Alan R ^aa   Schall, Ulrich ^aa   Schubert, Christian R ^aa   Schwab, Sibylle G ^aa   Scolnick, Edward M ^aa   Scott, Rodney J ^aa   Seidman, Larry J ^aa   Shi, Jianxin ^aa   Sigurdsson, Engilbert ^aa   Silagadze, Teimuraz ^aa   Silverman, Jeremy M ^aa   Sim, Kang ^aa   Slominsky, Petr ^aa   Smoller, Jordan W ^aa   So, Hon Cheong ^aa   Spencer, Chris C A ^aa   Stahl, Eli A ^aa   Stefansson, Hreinn ^aa   Steinberg, Stacy ^aa   Stogmann, Elisabeth ^aa   Straub, Richard E ^aa   Strengman, Eric ^aa   Scott Stroup, T ^aa   Subramaniam, Mythily ^aa   Suvisaari, Jaana ^aa   Svrakic, Dragan M ^aa   Szatkiewicz, Jin P ^aa   Söderman, Erik ^aa   Thirumalai, Srinivas ^aa   Toncheva, Draga ^aa   Tosato, Sarah ^aa   Veijola, Juha ^aa   Waddington, John ^aa   Walsh, Dermot ^aa   Wang, Dai ^aa   Wang, Qiang ^aa   Webb, Bradley T ^aa   Weiser, Mark ^aa   Wildenauer, Dieter B ^aa   Williams, Nigel M ^aa   Williams, Stephanie ^aa   Wolen, Aaron R ^aa   Wong, Emily H M ^aa   Wormley, Brandon K ^aa   Xi, Hualin Simon ^aa   Zai, Clement C ^aa   Zheng, Xuebin ^aa   Zimprich, Fritz ^aa   Wray, Naomi R ^aa   Stefansson, Kari ^aa   Visscher, Peter M ^aa   Adolfsson, Rolf ^aa   Andreassen, Ole A ^aa   Blackwood, Douglas H R ^aa   Bramon, Elvira ^aa   Buxbaum, Joseph D ^aa   Darvasi, Ariel ^aa   Domenici, Enrico ^aa   Ehrenreich, Hannelore ^aa   Esko, Tõnu ^aa   Gejman, Pablo V ^aa   Gill, Michael ^aa   Gurling, Hugh ^aa   Hultman, Christina M ^aa   Iwata, Nakao ^aa   Jablensky, Assen V ^aa   Jönsson, Erik G ^aa   Kendler, Kenneth S ^aa   Kirov, George ^aa   Knight, Jo ^aa   Lencz, Todd ^aa   Levinson, Douglas F ^aa   Li, Qingqin S ^aa   Liu, Jianjun ^aa   Malhotra, Anil K ^aa   McCarroll, Steven A ^aa   McQuillin, Andrew ^aa   Moran, Jennifer L ^aa   Mortensen, Preben B ^aa   Mowry, Bryan J ^aa   Ophoff, Roel A ^aa   Owen, Michael J ^aa   Palotie, Aarno ^aa   Pato, Carlos N ^aa   Petryshen, Tracey L ^aa   Posthuma, Danielle ^aa   Riley, Brien P ^aa   Sham, Pak C ^aa   Sklar, Pamela ^aa   Clair, David S ^aa   Weinberger, Daniel R ^aa   Wendland, Jens R ^aa   Werge, Thomas ^aa   Daly, Mark J ^aa   O'Donovan, Michael C ^aa   Sullivan, Patrick F ^y,z,aa   Keller, Matthew C ^a,aa   more..

^a UNIVERSITY OF COLORADO   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

^c BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^d VU UNIVERSITY AMSTERDAM   (Netherlands)

^e KING'S COLLEGE LONDON   (United Kingdom)

^f Aarhus   (Denmark)

^g AARHUS UNIVERSITY   (Denmark)

^h AARHUS UNIVERSITY HOSPITAL   (Denmark)

ⁱ UNIVERSITY OF BONN   (Germany)

^j UNIVERSITY OF BASEL   (Switzerland)

^k FORSCHUNGSZENTRUM JÜLICH   (Germany)

^l MEDICAL FACULTY MANNHEIM HEIDELBERG UNIVERSITY   (Germany)

^m ST JAMES S HOSPITAL   (Ireland)

ⁿ The Park   (Australia)

^o UNIVERSITY OF QUEENSLAND   (Australia)

^p MAX PLANCK INSTITUTE OF PSYCHIATRY   (Germany)

^q Germany 3 Munich Cluster for Systems Neurology   (Germany)

^r UNIVERSITY OF LIVERPOOL   (United Kingdom)

^s JENA UNIVERSITY HOSPITAL   (Germany)

^t TRINITY COLLEGE DUBLIN   (Ireland)

^u MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^v LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^w MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

^x MAYO CLINIC   (United States)

^y KAROLINSKA INSTITUTE   (Sweden)

^z UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^aa NONE

more..

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; AUTOZYGOSITY; CASE CONTROL STUDY; CONTROLLED STUDY; EDUCATIONAL STATUS; GENETIC ASSOCIATION; GENETIC PARAMETERS; GENOME ANALYSIS; HUMAN; INBREEDING; MAJOR CLINICAL STUDY; MOLECULAR PATHOLOGY; RELIGION; REPLICATION STUDY; RUNS OF HOMOZYGOSITY; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM; SOCIAL STATUS; URBAN POPULATION; ZYGOSITY; CONSANGUINITY; FEMALE; GENETICS; GENOME-WIDE ASSOCIATION STUDY; GENOMICS; HOMOZYGOTE; HUMAN GENOME; MALE; PATHOLOGY;

CONSANGUINITY; FEMALE; GENOME, HUMAN; GENOME-WIDE ASSOCIATION STUDY; GENOMICS; HOMOZYGOTE; HUMANS; MALE; POLYMORPHISM, SINGLE NUCLEOTIDE; SCHIZOPHRENIA;

EID: 84994314495     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1006343     Document Type: Article

References (46)

1. Darwin C, The effects of cross and self fertilisation in the vegetable kingdom. J. Murray; 1876.
2. Walsh B, Evolutionary Quantitative Genetics. Handbook of Statistical Genetics: Third Edition. 2008. p. 533–86.
3. Charlesworth B, Charlesworth D, The genetic basis of inbreeding depression. Genet Res. 1999;74(3):329–40. 10689809
4. Abaskuliev AA, Skoblo G V, Inbreeding, endogamy and exogamy among relatives of schizophrenia patients. Genetika. 1975;11(3):145–8.
5. Bulaeva OA, Pavlova TA, Bulaeva KB, The effect of inbreeding on accumulation of complex diseases in genetic isolates. Genetika. 2009;45(8):1096–104. 19769299
6. Mansour H, Fathi W, Klei L, Wood J, Chowdari K, Watson A, et al. Consanguinity and increased risk for schizophrenia in Egypt. Schizophr Res. 2010;120(1–3):108–12. doi: 10.1016/j.schres.2010.03.02620435442
7. Chaleby K, Tuma TA, Cousin marriages and schizophrenia in Saudi Arabia. Br J Psychiatry. 1987;150(APR.):547–9. 3664138
8. Gindilis VM, Gaĭnullin RG, Shmaonova LM, Genetico-demographic patterns of the prevalence of various forms of endogenous psychoses. Genetika. 1989;25(4):734–43. 2759447
9. Rudan I, Rudan D, Campbell H, Carothers A, Wright A, Smolej-Narancic N, et al. Inbreeding and risk of late onset complex disease. J Med Genet. 2003Dec1;40 (12): 925–32. doi: 10.1136/jmg.40.12.92514684692
10. Bittles AH, Neel J V, The costs of human inbreeding and their implications for variations at the DNA level. Nat Genet. 1994;8(2):117–21. doi: 10.1038/ng1094-1177842008
11. Keller MC, Visscher PM, Goddard ME, Quantification of inbreeding due to distant ancestors and its detection using dense single nucleotide polymorphism data. Genetics. 2011;189(1):237–49. doi: 10.1534/genetics.111.13092221705750
12. Vine AE, McQuillin A, Bass NJ, Pereira A, Kandaswamy R, Robinson M, et al. No evidence for excess runs of homozygosity in bipolar disorder. Psychiatr Genet. 2009;19(4):165–70. doi: 10.1097/YPG.0b013e32832a4faa19451863
13. Lencz T, Lambert C, DeRosse P, Burdick KE, Morgan TV, Kane JM, et al. Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. Proc Natl Acad Sci U S A. 2007;104(50):19942–7. doi: 10.1073/pnas.071002110418077426
14. Ku CS, Naidoo N, Teo SM, Pawitan Y, Regions of homozygosity and their impact on complex diseases and traits. Human Genetics. 2011. p. 1–15.
15. McQuillan R, Leutenegger AL, Abdel-Rahman R, Franklin CS, Pericic M, Barac-Lauc L, et al. Runs of Homozygosity in European Populations. Am J Hum Genet. 2008;83(3):359–72. doi: 10.1016/j.ajhg.2008.08.00718760389
16. Kirin M, McQuillan R, Franklin CS, Campbell H, Mckeigue PM, Wilson JF, Genomic runs of homozygosity record population history and consanguinity. PLoS One. 2010;5(11).
17. Enciso-Mora V, Hosking FJ, Houlston RS, Risk of breast and prostate cancer is not associated with increased homozygosity in outbred populations. Eur J Hum Genet. 2010;18(8):909–14. doi: 10.1038/ejhg.2010.5320407466
18. Spain SL, Cazier J- B, Houlston R, Carvajal-Carmona L, Tomlinson I, Colorectal cancer risk is not associated with increased levels of homozygosity in a population from the United Kingdom. Cancer Res. 2009;69(18):7422–9. doi: 10.1158/0008-5472.CAN-09-065919723657
19. Hosking FJ, Papaemmanuil E, Sheridan E, Kinsey SE, Lightfoot T, Roman E, et al. Genome-wide homozygosity signatures and childhood acute lymphoblastic leukemia risk. Blood. 2010;115(22):4472–7. doi: 10.1182/blood-2009-09-24448320231427
20. Keller MC, Simonson MA, Ripke S, Neale BM, Gejman P V, Howrigan DP, et al. Runs of homozygosity implicate autozygosity as a schizophrenia risk factor. PLoS Genet. 2012;8(4).
21. Thornton A, Lee P, Publication bias in meta-analysis: Its causes and consequences. J Clin Epidemiol. 2000;53(2):207–16. 10729693
22. Ioannidis JPA, Ioannidis JPA, Why most published research findings are false. PLoS Med. 2005;2(8):e124. doi: 10.1371/journal.pmed.002012416060722
23. Duncan LE, Keller MC, A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. American Journal of Psychiatry. 2011. p. 1041–9. doi: 10.1176/appi.ajp.2011.1102019121890791
24. Collaboration OS, Estimating the reproducibility of psychological science. Sci. 2015Aug28;349 (6251).
25. Ripke S, Neale BM, Corvin A, Walters JTR, Farh K-H, Holmans P a, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7. doi: 10.1038/nature1359525056061
26. Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969–76. doi: 10.1038/ng.94021926974
27. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D, Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38(8):904–9. doi: 10.1038/ng184716862161
28. Abdellaoui A, Hottenga JJ, Xiao X, Scheet P, Ehli EA, Davies GE, et al. Association between autozygosity and major depression: Stratification due to religious assortment. Behav Genet. 2013;43(6):455–67. doi: 10.1007/s10519-013-9610-123978897
29. Abdellaoui A, Hottenga JJ, Willemsen G, Bartels M, Van Beijsterveldt T, Ehli EA, et al. Educational attainment influences levels of homozygosity through migration and assortative mating. PLoS One. 2015;10(3).
30. Nalls MA, Guerreiro RJ, Simon-Sanchez J, Bras JT, Traynor BJ, Gibbs JR, et al. Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer’s disease. Neurogenetics. 2009;10(3):183–90. doi: 10.1007/s10048-009-0182-419271249
31. Sims R, Dwyer S, Harold D, Gerrish A, Hollingworth P, Chapman J, et al. No evidence that extended tracts of homozygosity are associated with Alzheimer’s disease. Am J Med Genet Part B Neuropsychiatr Genet. 2011;156(7):764–71.
32. Ghani M, Sato C, Lee JH, Reitz C, Moreno D, Mayeux R, et al. Evidence of recessive Alzheimer disease loci in a Caribbean Hispanic data set: genome-wide survey of runs of homozygosity. JAMA Neurol. 2013;70(10):1261–7. doi: 10.1001/jamaneurol.2013.354523978990
33. Assié G, LaFramboise T, Platzer P, Eng C, Frequency of germline genomic homozygosity associated with cancer cases. Jama. 2008;299(12):1437–45. doi: 10.1001/jama.299.12.143718364486
34. Ruderfer DM, Lim ET, Genovese G, Moran JL, Hultman CM, Sullivan PF, et al. No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia. Eur J Hum Genet. 2014;23(July):1–3.
35. Heron EA, Cormican P, Donohoe G, O’Neill FA, Kendler KS, Riley BP, et al. No evidence that runs of homozygosity are associated with schizophrenia in an Irish genome-wide association dataset. Schizophr Res. 2014;154(1–3):79–82. doi: 10.1016/j.schres.2014.01.03824560374
36. Power RA, Keller MC, Ripke S, Abdellaoui A, Wray NR, Sullivan PF, et al. A recessive genetic model and runs of homozygosity in major depressive disorder. Am J Med Genet Part B Neuropsychiatr Genet. 2014;165(2):157–66.
37. Sullivan PF, Spurious Genetic Associations. Biol Psychiatry. 2007;61(10):1121–6. doi: 10.1016/j.biopsych.2006.11.01017346679
38. Collins AL, Kim Y, Sklar P, O’Donovan MC, Sullivan PF, Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results. Psychol Med. Cambridge Univ Press; 2012;42(03):607–16.
39. Button KS, Ioannidis JP a, Mokrysz C, Nosek B a, Flint J, Robinson ESJ, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14(5):365–76. doi: 10.1038/nrn347523571845
40. Peng RD, Reproducible research and Biostatistics. Biostatistics. Biometrika Trust; 2009;10(3):405–8. doi: 10.1093/biostatistics/kxp01419535325
41. Makel MC, Plucker JA, Hegarty B, Replications in psychology research how often do they really occur?Perspect Psychol Sci. Sage Publications; 2012;7(6):537–42. doi: 10.1177/174569161246068826168110
42. The 1000 Genomes Project ConsortiumAn integrated map of genetic variation from 1,092 human genomes. Nature. 2012Nov1;491(7422):56–65. doi: 10.1038/nature1163223128226
43. Hao K, Chudin E, McElwee J, Schadt EE, Accuracy of genome-wide imputation of untyped markers and impacts on statistical power for association studies. BMC Genet. 2009;10:27. doi: 10.1186/1471-2156-10-2719531258
44. Consortium IH, A haplotype map of the human genome. Nature. Nature Publishing Group; 2005;437(7063):1299–320. doi: 10.1038/nature0422616255080
45. Howrigan DP, Simonson MA, Keller MC, Detecting autozygosity through runs of homozygosity: A comparison of three autozygosity detection algorithms. BMC Genomics. 2011. p. 460. doi: 10.1186/1471-2164-12-46021943305
46. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75. doi: 10.1086/51979517701901