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Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7

Abstract

Although the concept of meta-analysis of multiple linkage scans of a genetic trait is not new, it can be difficult to apply to published data given the lack of consistency in the presentation of linkage results. In complex inheritance common diseases, there are many instances where one or two studies meet genome-wide criteria for significant or suggestive linkage but several other studies do not show even nominally significant results with the same region. One possibility for resolving differences between study results would be to combine an available result parameter of several studies. We describe here a method of regional meta-analysis, the multiple-scan probability (MSP), which can be used on published results. It combines the reported P-values of individual studies, after correcting each value for the size of the region containing a minimum P-value. Analyses of the power of MSP and of its type I error rates are presented. The type I error rate is at least as low as that for a single genome scan and thus genome-wide significance criteria may be applied. We also demonstrate appropriate criteria for this type of meta-analysis when the most significant study is included, and when that study is used to define a region of interest and then excluded. In our simulations, meta-analysis is at least as powerful as pooling data. Finally, we apply this method of meta-analysis to the evidence for linkage of autism susceptibility loci and demonstrate evidence for a susceptibility locus at 7q.

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References

  1. Suarez BK, Hampe CL, Van Eerdewegh P . Problems of replicating linkage claims in psychiatry. In: Gershon ES, Cloninger CR (eds) Genetic Approaches to Mental Disorders American Psychiatric Press: Washington, DC 1994 23–46

    Google Scholar 

  2. Lander ES, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nature Genet 1995 11: 241–247

    Article  CAS  PubMed  Google Scholar 

  3. Dorr DA, Rice JP, Armstrong C, Reich T, Blehar M . A meta-analysis of chromosome 18 linkage data for bipolar illness Genet Epidemiol 1997 14: 617–622

    Article  CAS  PubMed  Google Scholar 

  4. Rice JP . The role of meta-analysis in linkage studies of complex traits Am J Med Genet 1997 74: 112–114

    Article  CAS  PubMed  Google Scholar 

  5. Guerra R, Etzel CJ, Goldstein DR, Sain SR . Meta-analysis by combining p-values: simulated linkage studies Genet Epidemiol 1999 17: S605–S609

    Article  PubMed  Google Scholar 

  6. Allison DB, Heo M . Meta-analysis of linkage data under worst-case conditions: a demonstration using the human OB region Genetics 1998 148: 859–865

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus Nature Genet 2000 26: 163–175

    Article  CAS  PubMed  Google Scholar 

  8. Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B et al. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2 Nature Genet 1996 13: 161–166

    Article  CAS  PubMed  Google Scholar 

  9. Hani EH, Hager J, Philippi A, Demenais F, Froguel P, Vionnet N . Mapping NIDDM susceptibility loci in French families: studies with markers in the region of NIDDM1 on chromosome 2q Diabetes 1997 46: 1225–1226

    Article  CAS  PubMed  Google Scholar 

  10. Ghosh S, Hauser ER, Magnuson VL, Valle T, Ally DS, Karanjawala ZE et al. A large sample of Finish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter J Clin Invest 1998 102: 704–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Badner JA, Goldin LR . Meta-analysis of linkage studies Genet Epidemiol 1999 17: S485–S490

    Article  PubMed  Google Scholar 

  12. Hedges LV, Olkin I . Statistical Methods for Meta-analysis Academic Press: San Francisco 1985

    Google Scholar 

  13. Fisher RA . Statistical Methods for Research Workers Oliver & Boyd: London 1932

    Google Scholar 

  14. Roberts SB, MacLean CJ, Neale MC, Eaves LJ, Kendler KS . Replication of linkage studies of complex traits: an examination of variation in location estimates Am J Hum Genet 1999 65: 876–884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Feingold E, Brown PO, Siegmund D . Gaussian models for genetic linkage analysis using complete high-resolution maps of identity by descent Am J Hum Genet 1993 53: 234–251

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Terwilliger JD, Ott J . SIMULATE 2.24 ftp://linkage.cpmc.columbia.edu/software/simulate

  17. Ott J . Computer-simulation methods in human linkage analysis Proc Natl Acad Sci USA 1989 86: 4175–4178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Weeks DE, Ott J, Lathrop GM . SLINK: a general simulation program for linkage analysis Am J Hum Genet 1990 47: A204

    Google Scholar 

  19. Cottingham RW Jr, Idury RM, Schaffer AA . Faster sequential genetic linkage computations Am J Hum Genet 1997 53: 252–263

    Google Scholar 

  20. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study Psychol Med 1995 25: 63–77

    Article  CAS  PubMed  Google Scholar 

  21. Bolton P, Macdonald H, Pickles A, Rios P, Goode S, Crowson M et al. A case-control family history study of autism J Child Psychol Psychiatry 1994 35: 877–900

    Article  CAS  PubMed  Google Scholar 

  22. International Molecular Genetic Study of Autism Consortium. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium Hum Mol Genet 1998 7: 571–578

  23. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study Hum Mol Genet 1999 8: 805–812

    Article  CAS  PubMed  Google Scholar 

  24. Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits Am J Hum Genet 1997 57: 439–454

    Google Scholar 

  25. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J et al. A genomic screen of autism: evidence for a multilocus etiology Am J Hum Genet 1999 65: 493–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL et al. An autosomal genomic screen for autism Am J Med Genet 1999 88: 609–615

    Article  CAS  PubMed  Google Scholar 

  27. Broman KW, Murray JC, Sheffield VC, White RL, Weber JL . Comprehensive human genetic maps: individual and sex-specific variation in recombination Am J Hum Genet 1998 63: 861–869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ashley-Koch A, Wolpert CM, Menold MM, Zaeem L, Basu S, Donnelly SL et al. Genetic studies of autistic disorder and chromosome 7 Genomics 1999 61: 227–236

    Article  CAS  PubMed  Google Scholar 

  29. Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests Am J Hum Genet 1997 61: 1179–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hauser ER, Bochnke M, Guo SW, Risch N . Affected sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations Genet Epidemiol 1996 13: 117–137

    Article  CAS  PubMed  Google Scholar 

  31. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified approach Am J Hum Genet 1996 58: 1347–1363

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a seed grant to JAB from the Howard Hughes Medical Institute.

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Correspondence to J A Badner.

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Badner, J., Gershon, E. Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7. Mol Psychiatry 7, 56–66 (2002). https://doi.org/10.1038/sj.mp.4000922

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