Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2005 Jul;117(2-3):160-7.
doi: 10.1007/s00439-005-1282-3. Epub 2005 Apr 21.

The Importance of Modelling Heterogeneity in Complex Disease: Application to NIMH Schizophrenia Genetics Initiative Data

Affiliations
Multicenter Study

The Importance of Modelling Heterogeneity in Complex Disease: Application to NIMH Schizophrenia Genetics Initiative Data

Elizabeth Holliday et al. Hum Genet. .

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 (alpha) 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 alpha only in aggregate data, while the second (HLOD-S) determines alpha 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.

Similar articles

See all similar articles

Cited by 2 articles

References

    1. Am J Hum Genet. 2000 Feb;66(2):567-75 - PubMed
    1. Mol Psychiatry. 2004 Aug;9(8):784-95 - PubMed
    1. Am J Med Genet. 1998 Jul 10;81(4):290-5 - PubMed
    1. Am J Med Genet. 1998 Jul 10;81(4):275-81 - PubMed
    1. Psychol Med Monogr Suppl. 1992;20:1-97 - PubMed

Publication types

LinkOut - more resources

Feedback