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Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis

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Abstract

To date, several susceptibility loci for systemic lupus erythematosus (SLE) have been identified by individual genome-wide scans, but many of these loci have shown inconsistent results across studies. Additionally, many individual studies are at the lower limit of acceptable power recommended for declaring significant linkage. The genome search meta-analysis (GSMA) has been proposed as a valid and robust method for combining several genome scan results. The aim of this study is to investigate whether there is any consistent evidence of linkage across multiple studies, and to identify novel SLE susceptibility loci by using GSMA method. Twelve genome scan results generated from nine independent studies have been used for the present GSMA. All together, the data consists of 605 families with 1,355 SLE affected individuals from three self-reported ethnicities; Caucasian, African-American, and Hispanic. For each study, the genome was divided into 120 bins (30 cM) and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies following which the significance was assessed by the permutation tests. The present study identified two genomic locations at 6p22.3–6p21.1 and 16p12.3–16q12.2 that met genome-wide significance (p<0.000417). The identified region at 6p22.3–6p21.1 contains the HLA region. The combined p-values using Fisher’s method also supported the significance in these regions. Clustering of significant adjacent bins was observed for chromosomes 6 and 16. Additionally, there are 12 other bins with two point-wise p-values (Psumrnk and Pord) <0.05, suggesting that these bin regions are highly likely to contain SLE susceptibility loci. Among them, present GSMA also identified two novel regions at 4q32.1–4q34.3 and 13q13.2–13q22.2. However, separate analysis using only Caucasian populations identified the strongest evidence for linkage at chromosome 6p21.1–6q15 (Psumrnk=0.00021). One interesting novel region suggests that 3q22.1–3q25.33 (Psumrnk=0.01376) may be an ethnicity-specific SLE linkage. In summary, the present GSMA have identified two statistically significant genomic regions that reconfirmed the SLE linkage at chromosomes 6 and 16.

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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

    Article  PubMed  CAS  Google Scholar 

  • Cantor RM, Yuan J, Napier S, Kono N, Grossman JM, Hahn BH, Tsao BP (2004) Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12–13, and 17q21–23 and novel evidence at 3p24, 10q23–24, 13q32, and 18q22–23. Arthritis Rheum 50:3203–3210

    Article  PubMed  CAS  Google Scholar 

  • Chiodini BD, Lewis CM (2003) Meta-analysis of 4 coronary heart disease genome-wide linkage studies confirms a susceptibility locus on chromosome 3q. Arterioscler Thromb Vasc Biol 23:1863–1868

    Article  PubMed  CAS  Google Scholar 

  • Cordell HJ (2001) Sample size requirements to control for stochastic variation in magnitude and location of allele-sharing linkage statistics in affected sibling pairs. Ann Hum Genet 65:491–502

    Article  PubMed  CAS  Google Scholar 

  • Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P, Walker A, Mack TM (1992) A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 35:311–318

    Article  PubMed  CAS  Google Scholar 

  • Demenais F, Kanninen T, Lindgren CM, Wiltshire S, Gaget S, Dandrieux C, Almgren P, Sjogren M, Hattersley A, Dina C, Tuomi T, McCarthy MI, Froguel P, Groop LC (2003) A meta-analysis of four European genome screens (GIFT Consortium) shows evidence for a novel region on chromosome 17p11.2–q22 linked to type 2 diabetes. Hum Mol Genet 12:1865–1873

    Article  PubMed  CAS  Google Scholar 

  • Feng XB, Shen N, Chen SL, Qian J, Wu H, Bao CD, Wang Y (2003) Susceptibility gene of systematic lupus erythematosus in 16q12 in Chinese cohort. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 20:27–30

    PubMed  CAS  Google Scholar 

  • Feng XB, Shen N, Luo WQ, Zhang LH, Qan J, Sun L (2004) OAZ gene polymorphism in Chinese patients with systemic lupus erythematosus. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 21:430–434

    PubMed  CAS  Google Scholar 

  • Fisher RA (1932) Statistical methods for research workers. 4th edn. Oliver and Boyd, Edinburgh

    Google Scholar 

  • Fisher SA, Lanchbury JS, Lewis CM (2003) Meta-analysis of four rheumatoid arthritis genome-wide linkage studies: confirmation of a susceptibility locus on chromosome 16. Arthritis Rheum 48:1200–1206

    Article  PubMed  CAS  Google Scholar 

  • Gaffney PM, Kearns GM, Shark KB, Ortmann WA, Selby SA, Malmgren ML, Rohlf KE, Ockenden TC, Messner RP, King RA, Rich SS, Behrens TW (1998) A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci USA 95:14875–14879

    Article  PubMed  CAS  Google Scholar 

  • Gaffney PM, Ortmann WA, Selby SA, Shark KB, Ockenden TC, Rohlf KE, Walgrave NL, Boyum WP, Malmgren ML, Miller ME, Kearns GM, Messner RP, King RA, Rich SS, Behrens TW (2000) Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sib-pair families. Am J Hum Genet 66:547–556

    Article  PubMed  CAS  Google Scholar 

  • Gillett CD, Langefeld CD, Williams AH, Ortmann WA, Graham RR, Rodne PR, Selby SA, Gaffney PM, Behrens TW, Moser KL (2005) Fine mapping chromosome 16q12 in a collection of 231 systemic lupus erythematosus sibpair and multiple families. Genes Immun 6:19–23

    PubMed  CAS  Google Scholar 

  • Goring HH, Terwilliger JD, Blangero J (2001) Large upward bias in estimation of locus-specific effects from genomewide scans. Am J Hum Genet 69:1357–1369

    Article  PubMed  CAS  Google Scholar 

  • Graham RR, Ortmann WA, Langfeld CD, Jawaheer D, Selby SA, Rodine PR, Baechler EC, Rohlf KE, Shark KB, Espe KJ, Green LE, Nair RP,Stuart PE, Elder JT, King RA, Moser KL, Gaffney PM, Bugawan TL, Erlich HA, Rich SS, Gregersen PK, Behrens TW (2002) Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am J Hum Genet 71:543–553

    Article  PubMed  CAS  Google Scholar 

  • Gray-McGuire C, Moser KL, Gaffney PM, Kelly J, Yu H, Olson JM, Jedrey CM, Jacobs KB, Kimberly RP, Neas BR, Rich SS, Behrens TW, Harley JB (2000) Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16–15.2. Am J Hum Genet 67:1460–1469

    Article  PubMed  CAS  Google Scholar 

  • Johansson CM, Zunec R, Garcia MA, Scherbarth HR, Tate GA, Paira S, Navarro SM, Perandones CE, Gamron S, Alvarellos A, Graf CE, Manni J, Berbotto GA, Palatnik SA, Catoggio LJ, Battagliotti CG, Sebastiani GD, Migliaresi S, Galeazzi M, Pons-Estel BA, Alarcon-Riquelme ME (2004) Chromosome 17p12–q11 harbors susceptibility loci for systemic lupus erythematosus. Hum Genet 115:230–238

    Article  PubMed  CAS  Google Scholar 

  • Koivukoski L, Fisher SA, Kanninen T, Lewis CM, von Wowern F, Hunt S, Kardia SL, Levy D, Perola M, Rankinen T, Rao DC, Rice T, Thiel BA, Melander O (2004) Meta-analysis of genome-wide scans for hypertension and blood pressure in Caucasians shows evidence of susceptibility regions on chromosomes 2 and 3. Hum Mol Genet 13:2325–2332

    Article  PubMed  CAS  Google Scholar 

  • Koskenmies S, Lahermo P, Julkunen H, Ollikainen V, Kere J, Widen E (2004) Linkage mapping of systemic lupus erythematosus (SLE) in Finnish families multiply affected by SLE. J Med Genet 41:e2–e5

    Article  PubMed  CAS  Google Scholar 

  • Levinson DF, Levinson MD, Segurado R, Lewis CM (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part I: methods and power analysis. Am J Hum Genet 73:17–33

    Article  PubMed  CAS  Google Scholar 

  • Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, O’Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O’Donovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 73:34–48

    Article  PubMed  CAS  Google Scholar 

  • Lindqvist AK, Steinsson K, Johanneson B, Kristjansdottir H, Arnasson A, Grondal G, Jonasson I, Magnusson V, Sturfelt G, Truedsson L, Svenungsson E, Lundberg I, Terwilliger JD, Gyllensten UB, Alarcon-Riquelme ME (2000) A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimmun 14:169–178

    Article  PubMed  CAS  Google Scholar 

  • Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, Asundi N, Bruner GR, Fox J, Kelly J, Henshall S, Bacino D, Dietz M, Hogue R, Koelsch G, Nightingale L, Shaver T, Abdou NI, Albert DA, Carson C, Petri M, Treadwell EL, James JA, Harley JB (1998) Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 95:14869–14874

    Article  PubMed  CAS  Google Scholar 

  • Nath SK, Quintero-Del-Rio AI, Kilpatrick J, Feo L, Ballesteros M, Harley JB (2004a) Linkage at 12q24 with systemic lupus erythematosus (SLE) is established and confirmed in Hispanic and European American families. Am J Hum Genet 74:73–82

    Article  PubMed  CAS  Google Scholar 

  • Nath SK, Namjou B, Hutchings D, Garriott CP, Pongratz C, Guthridge J, James JA (2004b) Systemic lupus erythematosus (SLE) and chromosome 16: confirmation of linkage to 16q12–13 and evidence for genetic heterogeneity. Eur J Hum Genet 12:668–672

    Article  PubMed  CAS  Google Scholar 

  • Ott J (1991) Analysis of human genetic linkage. John Hopkins University Press, Baltimore

    Google Scholar 

  • Province MA (2001) The significance of not finding a gene. Am J Hum Genet 69:660–663

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger JI Jr, Craddock N, DePaulo JR, Baron M, Gershon ES, Ekholm J, Cichon S, Turecki G, Claes S, Kelsoe JR, Schofield PR, Badenhop RF, Morissette J, Coon H, Blackwood D, McInnes LA, Foroud T, Edenberg HJ, Reich T, Rice JP, Goate A, McInnis MG, McMahon FJ, Badner JA, Goldin LR, Bennett P, Willour VL, Zandi PP, Liu J, Gilliam C, Juo SH, Berrettini WH, Yoshikawa T, Peltonen L, Lonnqvist J, Nothen MM, Schumacher J, Windemuth C, Rietschel M, Propping P, Maier W, Alda M, Grof P, Rouleau GA, Del Favero J, Van Broeckhoven C, Mendlewicz J, Adolfsson R, Spence MA, Luebbert H, Adams LJ, Donald JA, Mitchell PB, Barden N, Shink E, Byerley W, Muir W, Visscher PM, Macgregor S, Gurling H, Kalsi G, McQuillin A, Escamilla MA, Reus VI, Leon P, Freimer NB, Ewald H, Kruse TA, Mors O, Radhakrishna U, Blouin JL, Antonarakis SE, Akarsu N (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. Am J Hum Genet 73:49–62

    Article  PubMed  CAS  Google Scholar 

  • Shai R, Quismorio FP Jr, Li L, Kwon OJ, Morrison J, Wallace DJ, Neuwelt CM, Brautbar C, Gauderman WJ, Jacob CO (1999) Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 8:639–644

    Article  PubMed  CAS  Google Scholar 

  • Van Heel DA, Fisher SA, Kirby A, Daly MJ, Rioux JD, Lewis CM (2004) Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet 13:763–770

    Article  PubMed  Google Scholar 

  • Wandstrat A, Wakeland E (2001) The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat Immunol 2:802–809

    Article  PubMed  CAS  Google Scholar 

  • Wise LH, Lanchbury JS, Lewis CM (1999) Meta-analysis of genome searches. Ann Hum Genet 63(Pt 3):263–272

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge Dr. Cathryn Lewis, for her helpful comments and discussion. The authors also thank Ms. Summer Frank and Xana Kim for proofreading. This work was supported by the National Institutes of Health grants (AR048928, AI063622, RR020143, and AR049084).

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Correspondence to Swapan K. Nath.

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Lee, Y.H., Nath, S.K. Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis. Hum Genet 118, 434–443 (2005). https://doi.org/10.1007/s00439-005-0073-1

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