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

Holliday, E., Mowry, B., Chant, D., & Nyholt, D.R. (2005) The importance of modelling heterogeneity in complex disease: application to NIMH Schizophrenia Genetics Initiative data. Human Genetics, 117(2-3), pp. 160-167.

View at publisher


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.

Impact and interest:

7 citations in Scopus
Search Google Scholar™
8 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 92164
Item Type: Journal Article
Refereed: Yes
Additional Information: Holliday, Elizabeth
Mowry, Bryan
Chant, David
Nyholt, Dale
Multicenter Study
2005/04/22 09:00
Hum Genet. 2005 Jul;117(2-3):160-7. Epub 2005 Apr 21.
Keywords: Chromosomes, Human, Pair 10/*genetics, Chromosomes, Human, Pair 15/*genetics, Databases, Genetic, *Genetic Predisposition to Disease, Genotype, Humans, *Lod Score, Schizophrenia/*genetics
DOI: 10.1007/s00439-005-1282-3
ISSN: 0340-6717
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright Springer-Verlag 2005
Deposited On: 21 Jan 2016 04:50
Last Modified: 21 Jan 2016 04:50

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page