Skip to main content
SpringerLink
Log in

The role of large pedigrees in an era of high-throughput sequencing

  • Review Paper
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Rare variation is the current frontier in human genetics. The large pedigree design is practical, efficient, and well-suited for investigating rare variation. In large pedigrees, specific rare variants that co-segregate with a trait will occur in sufficient numbers so that effects can be measured, and evidence for association can be evaluated, by making use of methods that fully use the pedigree information. Evidence from linkage analysis can focus investigation, both reducing the multiple testing burden and expanding the variants that can be evaluated and followed up, as recent studies have shown. The large pedigree design requires only a small fraction of the sample size needed to identify rare variants of interest in population-based designs, and many highly suitable, well-understood, and available statistical and computational tools already exist. Samples consisting of large pedigrees with existing rich phenotype and genome scan data should be prime candidates for high-throughput sequencing in the search of the determinants of complex traits.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abecasis GR, Wigginton JE (2005) Handling marker–marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 77:754–767

    Article  PubMed  CAS  Google Scholar 

  • Almasy L, Blangero J (2004) Exploring positional candidate genes: linkage conditional on measured genotype. Behav Genet 34:173–177

    Article  PubMed  CAS  Google Scholar 

  • Amberger J, Bocchini C, Hamosh A (2011) A new face and new challenges for Online Mendelian Inheritance in man (OMIM (R)). Hum Mutat 32:564–567

    Article  PubMed  Google Scholar 

  • Bailey-Wilson JE, Wilson AF (2011) Linkage analysis in the next-generation sequencing era. Hum Hered 72:228–236

    Article  PubMed  CAS  Google Scholar 

  • Bodmer W, Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40:695–701

    Article  PubMed  CAS  Google Scholar 

  • Boehnke M (1994) Limits of resolution of genetic linkage studies: implications for positional cloning of human disease genes. Am J Hum Genet 55:379–390

    PubMed  CAS  Google Scholar 

  • Boehnke M, Cox N (1997) Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 61:423–429

    Article  PubMed  CAS  Google Scholar 

  • Botstein D, Risch N (2003) Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 33:228–237

    Article  PubMed  CAS  Google Scholar 

  • Botstein D, White RL, Skolnick M, Davis RW (1980) Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet 32:314–331

    PubMed  CAS  Google Scholar 

  • Bowden DW, An SS, Palmer ND, Brown WM, Norris JM, Haffner SM, Hawkins GA, Guo X, Rotter JI, Chen YDI, Wagenknecht LE, Langefeld CD (2010) Molecular basis of a linkage peak: exome sequencing and family-based analysis identify a rare genetic variant in the ADIPOQ gene in the IRAS family study. Hum Mol Genet 19:4112–4120

    Article  PubMed  CAS  Google Scholar 

  • Buetow K (1991) Influence of aberrant observations on high-resolution linkage analysis outcomes. Am J Hum Genet 49:985–994

    PubMed  CAS  Google Scholar 

  • Burdick JT, Chen WM, Abecasis GR, Cheung VG (2006) In silico method for inferring genotypes in pedigrees. Nat Genet 38:1002–1004

    Article  PubMed  CAS  Google Scholar 

  • Calafell F, Almasy L, Sabater-Lleal M, Buil A, Mordillo C, Ramirez-Soriano A, Sikora M, Souto JC, Blangero J, Fontcuberta J, Soria JM (2010) Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels. Hum Mol Genet 19:517–525

    Article  PubMed  CAS  Google Scholar 

  • Cheung CYK, Thompson EA, Wijsman EM (2010) In silico genotype imputation on large pedigrees. Genet Epidemiol 34:919

    Google Scholar 

  • Cheung CYK, Wijsman EM, Thompson EA (2011) Detection of genotype errors in dense markers on large pedigrees. International Congress of Human Genetics, Montreal

    Google Scholar 

  • Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305:869–872

    Article  PubMed  CAS  Google Scholar 

  • Collins FS (1991) Of needles and haystacks—finding human-disease genes by positional cloning. Clin Res 39:615–623

    PubMed  CAS  Google Scholar 

  • Collins FS, Guyer MS, Chakravarti A (1997) Variations on a theme: cataloging human DNA sequence variation. Science 278:1580–1581

    Article  PubMed  CAS  Google Scholar 

  • Cruchaga C, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM (2012) Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PLoS One 7:e31039

    Article  PubMed  CAS  Google Scholar 

  • Daw EW, Heath SC, Wijsman EM (1999) Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer’s disease pedigrees. Am J Hum Genet 64:839–851

    Article  PubMed  CAS  Google Scholar 

  • Ehm MG, Kimmel M, Cottingham RW (1996) Error detection for genetic data, using likelihood methods. Am J Hum Genet 58:225–234

    PubMed  CAS  Google Scholar 

  • Elston RC, Stewart J (1971) A general model for the genetic analysis of pedigree data. Hum Hered 21:523–542

    Article  PubMed  CAS  Google Scholar 

  • Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O (2011) Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res 21:658–664

    Article  PubMed  CAS  Google Scholar 

  • Flint J, Mackay TFC (2009) Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res 19:723–733

    Article  PubMed  CAS  Google Scholar 

  • Gagnon F, Roslin NM, Lemire M (2011) Successful identification of rare variants using oligogenic segregation analysis as a prioritizing tool for whole-exome sequencing studies. BMC Proc 5:S11

    Article  PubMed  Google Scholar 

  • Gerrish A, Russo G, Richards A, Moskvina V, Ivanov D, Harold D, Sims R, Abraham R, Hollingworth PCJ, Hamshere M, Pahwa JS, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Johnston JA, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Kölsch H, Heun R, Schürmann B, Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Davies G, Harris SE, Starr JM, Deary IJ, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Jones L, Holmans PA, O’Donovan MC, Owen MJ, Williams J (2012) The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer’s disease. J Alzheimers Dis 28:377–387

    PubMed  CAS  Google Scholar 

  • Gorlov IP, Gorlova OY, Frazier ML, Spitz MR, Amos CI (2011) Evolutionary evidence of the effect of rare variants on disease etiology. Clin Genet 79:199–206

    Article  PubMed  CAS  Google Scholar 

  • Haldane JBS, Smith CAB (1947) A new estimate of the linkage between the genes for colour-blindness and haemophilia in man. Ann Eugen 14:10–31

    PubMed  CAS  Google Scholar 

  • Heath SC (1997) Markov Chain Monte Carlo segregation and linkage analysis for oligogenic models. Am J Hum Genet 61:748–760

    Article  PubMed  CAS  Google Scholar 

  • Hedin CR, Stagg AJ, Whelan K, Lindsay JO (2012) Family studies in Crohn’s disease: new horizons in understanding disease pathogenesis, risk and prevention. Gut 61:311–318

    Article  PubMed  CAS  Google Scholar 

  • Hershberger RE, Morales A, Siegfried JD (2010) Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med 12:655–667

    Article  PubMed  CAS  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 Nat Acad Sci USA 106:9362–9367

    Article  PubMed  CAS  Google Scholar 

  • Hokanson JE, Brunzell JD, Jarvik GP, Wijsman EM, Austin MA (1999) Linkage of low-density lipoprotein size to the lipoprotein lipase gene in heterozygous lipoprotein lipase deficiency. Am J Hum Genet 64:608–618

    Article  PubMed  CAS  Google Scholar 

  • Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983

    Article  Google Scholar 

  • Ionita-Laza I, Ottman R (2011) Study designs for identification of rare disease variants in complex diseases: the utility of family-based designs. Genetics 189:1061–U500

    Google Scholar 

  • Jaquish CE (2007) The Framingham Heart Study, on its way to becoming the gold standard for cardiovascular genetic epidemiology? BMC Med Genet 8:63

    Google Scholar 

  • Jarvik GP, Brunzell JD, Austin MA, Krauss RM, Motulsky AG, Wijsman EM (1994) Genetic predictors of FCHL in four large pedigrees: influence of ApoB level major locus predicted genotype and LDL subclass phenotype. Arterioscler Thromb Vasc Biol 14:1687–1694

    Article  CAS  Google Scholar 

  • Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389

    Article  PubMed  CAS  Google Scholar 

  • Koepke H, Thompson EA (2010) Efficient testing operations on dynamic graph structures using strong hash functions. Department of Statistics, technical reports. University of Washington, Seattle

  • Lee ET, Welty TK, Fabsitz R, Cowan LD, Le NA, Oopik AJ, Cucchiara AJ, Savage PJ, Howard BV (1990) The Strong Heart-Study—a study of cardiovascular-disease in American–Indians—design and methods. Am J Epidemiol 132:1141–1155

    PubMed  CAS  Google Scholar 

  • Leibon G, Rockmore DN, Pollak MR (2008) A SNP streak model for the identification of genetic regions identical-by-descent. Stat Appl Genet Mol Biol 7:16

    Google Scholar 

  • Leigh SEA, Foster AH, Whittall RA, Hubbart CS, Humphries SE (2008) Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 72:485–498

    Article  PubMed  CAS  Google Scholar 

  • Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu YH, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Willer C, Sanna S, Abecasis G (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10:387–406

    Article  PubMed  CAS  Google Scholar 

  • Manolio TA, Brooks LD, Collins FS (2008) A HapMap harvest of insights into the genetics of common disease. J Clin Invest 118:1590–1605

    Article  PubMed  CAS  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 TFC, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753

    Article  PubMed  CAS  Google Scholar 

  • Marchani EE, Wijsman EM (2011) Estimation and visualization of identity-by-descent within pedigrees simplifies interpretation of complex trait analysis. Hum Hered 72:289–297

    Article  PubMed  Google Scholar 

  • Markus B, Birk OS, Geiger D (2011) Integration of SNP genotyping confidence scores in IBD inference. Bioinformatics 27:2880–2887

    Article  PubMed  CAS  Google Scholar 

  • Matise TC, Chen F, Chen WW, De la Vega FM, Hansen M, He CS, Hyland FCL, Kennedy GC, Kong XY, Murray SS, Ziegle JS, Stewart WCL, Buyske S (2007) A second-generation combined linkage-physical map of the human genome. Genome Res 17:1783–1786

    Article  PubMed  CAS  Google Scholar 

  • McClellan J, King MC (2010) Genetic heterogeneity in human disease. Cell 141:210–217

    Article  PubMed  CAS  Google Scholar 

  • Miki Y, Swensen J, Shattuckeidens D, Futreal PA, Harshman K, Tavtigian S, Liu QY, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugenstrano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannonalbright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH (1994) A strong candidate for the breast and ovarian-cancer susceptibility gene BRCA1. Science 266:66–71

    Article  PubMed  CAS  Google Scholar 

  • Morris JC (2011) Dominantly Inherited Alzheimer Network (DIAN): registry characteristics and biomarker findings. Neurology 76:A416–A416

    Google Scholar 

  • Morton NE (1955) Sequential tests for the detection of linkage. Am J Hum Genet 7:277–318

    PubMed  CAS  Google Scholar 

  • Mukhopadhyay N, Buxbaum SG, Weeks DE (2004) Comparative study of multipoint methods for genotype error detection. Hum Hered 58:175–189

    Article  PubMed  Google Scholar 

  • Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S (2010) Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 363:2220–2227

    Article  PubMed  CAS  Google Scholar 

  • Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, Bamshad M, Nickerson DA, Shendure J (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461:272–U153

    Google Scholar 

  • Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ (2010) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42:30–U41

    Google Scholar 

  • Norton N, Li DX, Rieder MJ, Siegfried JD, Rampersaud E, Zuchner S, Mangos S, Gonzalez-Quintana J, Wang LB, McGee S, Reiser J, Martin E, Nickerson DA, Hershberger RE (2011) Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet 88:273–282

    Article  PubMed  CAS  Google Scholar 

  • Ott J (1974) Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet 26:588–597

    PubMed  CAS  Google Scholar 

  • Ott J (1992) Strategies for characterizing highly polymorphic markers in human gene mapping. Am J Hum Genet 51:283–290

    PubMed  CAS  Google Scholar 

  • Pajukanta P, Allayee H, Krass KL, Kuraishy A, Soro A, Lilja HE, Mar R, Taskinen MR, Nuotio I, Laakso M, Rotter JI, de Bruin TWA, Cantor RM, Lusis AJ, Peltonen L (2003) Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q. Am J Hum Genet 72:903–917

    Article  PubMed  CAS  Google Scholar 

  • Penrose LS (1935) The detection of autosomal linkage in data which consist of pairs of brothers and sisters of unspecified parentage. Ann Eugen 6:133–138

    Google Scholar 

  • Raskind WH, Matsushita M, Peter B, Biberston J, Wolff J, Lipe H, Burbank R, Bird TD (2009) Familial dyskinesia and facial myokymia (FDFM): follow-up of a large family and linkage to chromosome 3p21–3q21. Am J Med Genet Part B Neuropsychiat Genet 150B:570–574

    Article  CAS  Google Scholar 

  • Raskind WH, Chen YZ, Matsushita MM, Robertson PD, Rieder M, Girirajan S, Lipe H, Eichler EE, Nickerson DA, Bird TD (2011) Linkage and single exome analyses identify ADCY5 as the gene for familial dyskinesia with facial myokymia. Int Congr Hum Genet, Montreal

    Google Scholar 

  • Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA, Milewicz DM (2011) Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res 109:680–U220

    Google Scholar 

  • Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou J-L, Drumm ML, Iannuzzi MC, Collins FS, Tsui L-C (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073

    Google Scholar 

  • Risch N (2000) Searching for genetic determinants in the new millennium. Nature 405:847–856

    Article  PubMed  CAS  Google Scholar 

  • Roach JC, Glusman G, Smit AFA, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ (2010) Analysis of genetic inheritance in a family Quartet by whole-genome sequencing. Science 328:636–639

    Article  PubMed  CAS  Google Scholar 

  • Roeder K, Bacanu SA, Wasserman L, Devlin B (2006) Using linkage genome scans to improve power of association in genome scans. Am J Hum Genet 78:243–252

    Article  PubMed  CAS  Google Scholar 

  • Rosenthal EA, Ronald J, Rothstein J, Rajagopalan R, Ranchalis J, Wolfbauer G, Albers JJ, Brunzell JD, Motulsky AG, Rieder MJ, Nickerson DA, Wijsman EM, Jarvik GP (2011) Linkage and association of phospholipid transfer protein activity to LASS4. J Lipid Res 52:1837–1846

    Google Scholar 

  • Sanna S, Li BS, Mulas A, Sidore C, Kang HM, Jackson AU, Piras MG, Usala G, Maninchedda G, Sassu A, Serra F, Palmas MA, Wood WH, Njolstad I, Laakso M, Hveem K, Tuomilehto J, Lakka TA, Rauramaa R, Boehnke M, Cucca F, Uda M, Schlessinger D, Nagaraja R, Abecasis GR (2011) Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. Plos Genet 7:e1002198

    Google Scholar 

  • Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Dasilva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760

    Article  PubMed  CAS  Google Scholar 

  • Sieh W, Yu C-E, Bird TD, Schellenberg GD, Wijsman EM (2007) Accounting for linkage disequilibrium among markers in linkage analysis: impact of haplotype frequency estimation and molecular haplotypes for a gene in a candidate region for Alzheimer’s disease. Hum Hered 63:26–34

    Article  PubMed  Google Scholar 

  • Sillanpaa MJ, Auranen K (2004) Replication in genetic studies of complex traits. Ann Hum Genet 68:646–657

    Article  PubMed  CAS  Google Scholar 

  • Simpson CL, Justice CM, Krishnan M, Wojciechowski R, Sung H, Cai J, Green T, Lewis D, Behneman D, Wilson AF, Bailey-Wilson JE (2011) Old lessons learned anew: family-based methods for detecting genes responsible for quantitative and qualitative traits in the Genetic Analysis Workshop 17 mini-exome sequence data. BMC Proc 5:S83

    Article  PubMed  Google Scholar 

  • Smith KR, Bromhead CJ, Hildebrand MS, Shearer AE, Lockhart PJ, Najmabadi H, Leventer RJ, McGillivray G, Amor DJ, Smith RJ, Bahlo M (2011) Reducing the exome search space for Mendelian diseases using genetic linkage analysis of exome genotypes. Genome Biol 12:R85

    Google Scholar 

  • Sobel E, Lange K (1993) Metropolis sampling in pedigree analysis. Stat Methods Med Res 2:263–282

    Google Scholar 

  • Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58:1323–1337

    PubMed  CAS  Google Scholar 

  • Sobel E, Sengul H, Weeks DE (2001) Multipoint estimation of identity-by-descent probabilities at arbitrary positions among marker loci on general pedigrees. Hum Hered 52:121–131

    Article  PubMed  CAS  Google Scholar 

  • Southgate L, Machado RD, Snape KM, Primeau M, Dafou D, Ruddy DM, Branney PA, Fisher M, Lee GJ, Simpson MA, He Y, Bradshaw TY, Blaumeiser B, Winship WS, Reardon W, Maher ER, FitzPatrick DR, Wuyts W, Zenker M, Lamarche-Vane N, Trembath RC (2011) Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies. Am J Hum Genet 88:574–585

    Article  PubMed  CAS  Google Scholar 

  • Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Magi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segre AV, Estrada K, Liang LM, Nemesh J, Park JH, Gustafsson S, Kilpelanen TO, Yang JA, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li SX, Moffatt MF, Myers RH, Narisu N, Perry JRB, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi JX, Thiering E, Alavere H, Alibrandi MTS, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AIF, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–U53

    Google Scholar 

  • Sturtevant AH (1913) The linear arrangement of six sex-linked factors in Drosophila as shown by their mode of association. J Exp Zool 14:43–59

    Article  Google Scholar 

  • Thoday JM (1961) Location of polygenes. Nature 191:368–370

    Article  Google Scholar 

  • Thomas A (2007) Towards linkage analysis with markers in linkage disequilibrium by graphical modelling. Hum Hered 64:16–26

    Article  PubMed  CAS  Google Scholar 

  • Thomas A, Gutin A, Abkevich V, Bansal A (2000) Multilocus linkage analysis by blocked Gibbs sampling. Stat Comput 10:259–269

    Article  Google Scholar 

  • Thomas A, Camp NJ, Farnham JM, Allen-Brady K, Cannon-Albright LA (2008) Shared genomic segment analysis. Mapping disease predisposition genes in extended pedigrees using SNP genotype assays. Ann Hum Genet 72:279–287

    Article  PubMed  CAS  Google Scholar 

  • Thompson EA (1994) Monte Carlo likelihood in the genetic mapping of complex traits. Philos Trans R Soc B 344:345–351

    Article  CAS  Google Scholar 

  • Thompson EA (2005) MCMC in the analysis of genetic data on pedigrees. In: Kendall WS, Wang JS, Liang F (eds) Markov chain Monte Carlo: innovations and applications. World Scientific Publishing Company, Singapore

    Google Scholar 

  • Thompson EA (2011) The structure of genetic linkage data: from LIPED to 1M SNPs. Hum Hered 71:86–96

    Article  PubMed  Google Scholar 

  • Tong LP, Thompson E (2008) Multilocus lod scores in large pedigrees: combination of exact and approximate calculations. Hum Hered 65:142–153

    Article  PubMed  Google Scholar 

  • Varilo T, Peltonen L (2004) Isolates and their potential use in complex gene mapping efforts—commentary. Curr Opin Genet Dev 14:316–323

    Article  PubMed  CAS  Google Scholar 

  • Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, Jiang H, Zhang P, Shen L, Guo JF, Li N, Li YR, Lei LF, Zhou J, Du J, Zhou YF, Pan Q, Wang J, Wang J, Li RQ, Tang BS (2010) TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain 133:3510–3518

    Article  PubMed  Google Scholar 

  • Weedon MN, Hastings R, Caswell R, Xie WJ, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S (2011) Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet 89:308–312

    Article  PubMed  CAS  Google Scholar 

  • Wijsman EM (1987) A deductive method of haplotype analysis in pedigrees. Am J Hum Genet 41:356–373

    PubMed  CAS  Google Scholar 

  • Wijsman EM, Amos CI (1997) Genetic analysis of simulated oligogenic traits in nuclear and extended pedigrees: summary of GAW10 contributions. Genet Epidemiol 14:719–735

    Article  PubMed  CAS  Google Scholar 

  • Wijsman EM, Rothstein JH, Thompson EA (2006) Multipoint linkage analysis with many multiallelic or dense diallelic markers: MCMC provides practical approaches for genome scans on general pedigrees. Am J Hum Genet 79:846–858

    Article  PubMed  CAS  Google Scholar 

  • Wijsman EM, Sung YJ, Buil A (2007) Summary of GAW15: group 9 linkage analysis of the CEPH expression data. Genet Epidemiol 31:S75–S85

    Article  PubMed  Google Scholar 

  • Wijsman EM, Rothstein JH, Igo RP, Brunzell JD, Motulsky AG, Jarvik GP (2010) Linkage and association analyses identify a candidate region for apoB level on chromosome 4q32.3 in FCHL families. Hum Genet 127:705–719

    Article  PubMed  CAS  Google Scholar 

  • Wilcox MA, Pugh EW, Zhang H, Zhong X, Levinson DF, Kennedy GC, Wijsman EM (2005) Comparison of single-nucleotide polymorphisms and microsatellite markers for linkage analysis in the COGA and simulated data sets for Genetic Analysis Workshop 14: presentation groups 1, 2, and 3. Genet Epidemiol 29(Suppl 1):S7–S28

    Article  PubMed  Google Scholar 

  • Wilson AF, Ziegler A (2011) Lessons learned from Genetic Analysis Workshop 17: transitioning from genome-wide association studies to whole-genome statistical genetic analysis. Genet Epidemiol 35:S107–S114

    Article  PubMed  Google Scholar 

  • Wright AF, Carothers AD, Pirastu M (1999) Population choice in mapping genes for complex diseases. Nat Genet 23:397–404

    Article  PubMed  CAS  Google Scholar 

  • Yazbek SN, Buchner DA, Geisinger JM, Burrage LC, Spiezio SH, Zentner GE, Hsieh CW, Scacheri PC, Croniger CM, Nadeau JH (2011) Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis. Genome Res 21:1065–1073

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by NIH grants GM046255, AG005136, HD054562, HD055782, MH092367, and AG039700.

Author information

Authors and Affiliations

  1. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Ellen M. Wijsman

  2. Division of Medical Genetics, Department of Medicine, University of Washington, Box 357720, Seattle, WA, 98195-7720, USA

    Ellen M. Wijsman

  3. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    Ellen M. Wijsman

Authors
  1. Ellen M. Wijsman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ellen M. Wijsman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wijsman, E.M. The role of large pedigrees in an era of high-throughput sequencing. Hum Genet 131, 1555–1563 (2012). https://doi.org/10.1007/s00439-012-1190-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-012-1190-2

Keywords

Search

Navigation