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 Holliday
  • Bryan Mowry
  • David Chant
  • Dale Nyholt
Original Investigation

Abstract

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 (LODexp)—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 LODexp 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 LODexp. 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.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Elizabeth Holliday
    • 1
    • 2
    • 3
  • 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

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