Human Genetics

, Volume 117, Issue 2–3, pp 160–167 | Cite as

The importance of modelling heterogeneity in complex disease: application to NIMH Schizophrenia Genetics Initiative data

  • Elizabeth HollidayEmail author
  • Bryan Mowry
  • David Chant
  • Dale Nyholt
Original Investigation


As for other complex diseases, linkage analyses of schizophrenia (SZ) have produced evidence for numerous chromosomal regions, with inconsistent results reported across studies. The presence of locus heterogeneity appears likely and may reduce the power of linkage analyses if homogeneity is assumed. In addition, when multiple heterogeneous datasets are pooled, inter-sample variation in the proportion of linked families (α) may diminish the power of the pooled sample to detect susceptibility loci, in spite of the larger sample size obtained. We compare the significance of linkage findings obtained using allele-sharing LOD scores (LOD exp )—which assume homogeneity—and heterogeneity LOD scores (HLOD) in European American and African American NIMH SZ families. We also pool these two samples and evaluate the relative power of the LOD exp and two different heterogeneity statistics. One of these (HLOD-P) estimates the heterogeneity parameter α only in aggregate data, while the second (HLOD-S) determines α separately for each sample. In separate and combined data, we show consistently improved performance of HLOD scores over LOD exp . Notably, genome-wide significant evidence for linkage is obtained at chromosome 10p in the European American sample using a recessive HLOD score. When the two samples are combined, linkage at the 10p locus also achieves genome-wide significance under HLOD-S, but not HLOD-P. Using HLOD-S, improved evidence for linkage was also obtained for a previously reported region on chromosome 15q. In linkage analyses of complex disease, power may be maximised by routinely modelling locus heterogeneity within individual datasets, even when multiple datasets are combined to form larger samples.


Recessive Model Locus Heterogeneity Suggestive Linkage African American Sample Marker Allele Frequency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are grateful to all members of the NIMH Schizophrenia Genetics Initiative for establishing this beneficial resource.


  1. Abreu PC, Greenberg DA, Hodge SE (1999) Direct power comparisons between simple LOD scores and NPL scores for linkage analysis in complex diseases. Am J Hum Genet 65:847–857Google Scholar
  2. American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn, revised edn. American Psychiatric Association Press, Washington DCGoogle Scholar
  3. Camp NJ, Farnham JM (2001) Correcting for multiple analyses in genomewide linkage studies. Ann Hum Genet 65:577–582Google Scholar
  4. Cheverud JM (2001) A simple correction for multiple comparisons in interval mapping genome scans. Heredity 87:52–58Google Scholar
  5. Cloninger CR, Kaufmann CA, Faraone SV, Malaspina D, Svrakic DM, Harkavy-Friedman J, Suarez BK, Matise TC, Shore D, Lee H, Hampe CL, Wynne D, Drain C, Markel PD, Zambuto CT, Schmitt K, Tsuang MT (1998) Genome-wide search for schizophrenia susceptibility loci: the NIMH genetics initiative and millennium consortium. Am J Med Genet 81:275–281Google Scholar
  6. Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P (2001) Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families. Am J Hum Genet 69:820–830Google Scholar
  7. Durner M, Vieland VJ, Greenberg DA (1999) Further evidence for the increased power of LOD scores compared with nonparametric methods. Am J Hum Genet 64:281–289Google Scholar
  8. Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez B, Hampe C, Zambuto CT, Schmitt K, Meyer J, Markel P, Lee H, Harkavy Friedman J, Kaufmann C, Cloninger CR, Tsuang MT (1998) Genome scan of European-American schizophrenia pedigrees: results of the NIMH genetics initiative and millennium consortium. Am J Med Genet 81:290–295Google Scholar
  9. Faraway JJ (1993) Distribution of the admixture test for the detection of linkage under heterogeneity. Genet Epidemiol 10:75–83Google Scholar
  10. Finch SJ, Chen CH, Gordon D, Mendell NR (2001) A study comparing precision of the maximum multipoint heterogeneity LOD statistic to three model-free multipoint linkage methods. Genet Epidemiol 21:315–325Google Scholar
  11. Freedman R, Leonard S, Olincy A, Kaufmann CA, Malaspina D, Cloninger CR, Svrakic D, Faraone SV, Tsuang MT (2001) Evidence for the multigenic inheritance of schizophrenia. Am J Med Genet 105:794–800Google Scholar
  12. Greenberg DA, Abreu PC (2001) Determining trait locus position from multipoint analysis: accuracy and power of three different statistics. Genet Epidemiol 21:299–314Google Scholar
  13. Greenberg DA, Abreu P, Hodge SE (1998) The power to detect linkage in complex disease by means of simple LOD-score analyses. Am J Hum Genet 63:870–879Google Scholar
  14. Gudbjartsson DF, Jonasson K, Frigge ML, Kong A (2000) Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25:12–13Google Scholar
  15. Hodge SE, Abreu PC, Greenberg DA (1997) Magnitude of type I error when single-locus linkage analysis is maximized over models: a simulation study. Am J Hum Genet 60:217–227Google Scholar
  16. Huang J, Vieland VJ (2001) Comparison of “model-free” and “model-based” linkage statistics in the presence of locus heterogeneity: single data set and multiple data set applications. Hum Hered 51:217–225Google Scholar
  17. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A (1992) Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 20:1–97Google Scholar
  18. Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD, Meyer J, Zambuto CT, Schmitt K, Matise TC, Harkavy Friedman JM, Hampe C, Lee H, Shore D, Wynne D, Faraone SV, Tsuang MT, Cloninger CR (1998) NIMH genetics initiative millenium schizophrenia consortium: linkage analysis of African-American pedigrees. Am J Med Genet 81:282–289Google Scholar
  19. Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61:1179–1188Google Scholar
  20. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247Google Scholar
  21. Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247Google Scholar
  22. Leal SM, Ott J (2000) Effects of stratification in the analysis of affected-sib-pair data: benefits and costs. Am J Hum Genet 66:567–575Google Scholar
  23. Levinson DF, Mowry BJ (2000) Genetics of schizophrenia. In: Pfaff D, Berrettini W, Maxson S, Joh T (eds) Genetic influences on neural and behavioural functions. CRC Press, New York, pp 47–82Google Scholar
  24. Mowry BJ, Holmans PA, Pulver AE, Gejman PV, Riley B, Williams NM, Laurent C, Schwab SG, Wildenauer DB, Bauche S, Owen MJ, Wormley B, Sanders AR, Nestadt G, Liang KY, Duan J, Ribble R, Norton N, Soubigou S, Maier W, Ewen-White KR, DeMarchi N, Carpenter B, Walsh D, Williams H, Jay M, Albus M, Nertney DA, Papadimitriou G, O’Neill A, O’Donovan MC, Deleuze JF, Lerer FB, Dikeos D, Kendler KS, Mallet J, Silverman JM, Crowe RR, Levinson DF (2004) Multicenter linkage study of schizophrenia loci on chromosome 22q. Mol Psychiatry 9:784–95Google Scholar
  25. Nurnberger JI Jr, Blehar MC, Kaufmann CA, York Cooler C, Simpson SG, Harkavy Friedman J, Severe JB, Malaspina D, Reich T (1994) Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Special issue: Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 51:849–859Google Scholar
  26. Ott J (1999) Analysis of human genetic linkage, 3rd edn. The John Hopkins University Press, BaltimoreGoogle Scholar
  27. Owen MJ, O’Donovan MC, Gottesman II (2002) Schizophrenia. In: McGuffin P, Owen MJ, Gottesman II (eds) Psychiatric genetics and genomics. Oxford University Press, Oxford, pp247–266Google Scholar
  28. Pal DK, Durner M, Greenberg DA (2001) Effect of misspecification of gene frequency on the two-point LOD score. Eur J Hum Genet 9:855–859Google Scholar
  29. Vieland VJ, Logue M (2002) HLODs, trait models, and ascertainment: implications of admixture for parameter estimation and linkage detection. Hum Hered 53:23–35Google Scholar
  30. Vieland VJ, Wang K, Huang J (2001) Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-based linkage methods for affected sib pair data. Hum Hered 51:199–208Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Elizabeth Holliday
    • 1
    • 2
    • 3
    Email author
  • Bryan Mowry
    • 1
    • 2
  • David Chant
    • 1
    • 2
  • Dale Nyholt
    • 3
  1. 1.Queensland Centre for Mental Health ResearchLevel 3, Dawson House, The Park, Centre for Mental HealthWacolAustralia
  2. 2.Department of PsychiatryUniversity of QueenslandBrisbaneAustralia
  3. 3.Queensland Institute of Medical Research, P.O. Royal Brisbane HospitalBrisbaneAustralia

Personalised recommendations