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Genetic Modeling in Twin Samples

Timothea Toulopoulou, PhD; Marco Picchioni, MRCP, MRCPsych; Fruhling Rijsdijk, PhD; Mei Hua-Hall, PhD; Ulrich Ettinger, PhD; Pak Sham, MD, PhD; Robin Murray, MD, DSc

Arch Gen Psychiatry. 2007;64(12):1348-1355.

Context  The use of endophenotypes, biological traits that increase the liability to a disorder, represents one strategy to facilitate the detection of susceptibility genes for complex behavioral disorders such as schizophrenia. Establishing that a candidate trait is both heritable and linked genetically to schizophrenia is integral to its validity as an endophenotypic marker. Neurocognitive deficits are among the most promising indicators of increased risk for schizophrenia; however, it is not clear to what extent these deficits are genetically linked to the disorder.

Objectives  To quantify the genetic and environmental contributions to the variability of selected neurocognitive measures and to estimate the genetic relationship between these and schizophrenia.

Design  Genetic model fitting to monozygotic and dizygotic twin data.

Setting  United Kingdom psychiatric research institute.

Participants  Two hundred sixty-seven monozygotic and dizygotic twins concordant and discordant for schizophrenia, and healthy monozygotic and dizygotic control twin pairs.

Main Outcome Measures  The heritabilities of intelligence, working memory, processing speed, perceptual organization, and verbal comprehension were estimated, and the genetic relationship between each of these and schizophrenia was quantified.

Results  Genetic influences contributed substantially to all of the cognitive domains, but intelligence and working memory were the most heritable. A significant correlation was found between intelligence and schizophrenia (r = –0.61; 95% confidence interval, –0.71 to –0.48), with shared genetic variance accounting for 92% of the covariance between the two. Genetic influences also explained most of the covariance between working memory and schizophrenia. Significant but lesser portions of covariance between the other cognitive domains and schizophrenia were also found to be genetically shared. Environmental effects, although separately linked to neurocognition and schizophrenia, did not generally contribute to their covariance.

Conclusion  Genomewide searches using factorial designs stratifying for levels of intelligence and working memory will assist in the search for finding quantitative trait loci for schizophrenia.

Author Affiliations: Department of Psychiatry (Dr Toulopoulou) and Psychology Research Laboratory, McLean Hospital (Dr Hua-Hall), Harvard Medical School, Boston, Massachusetts; Department of Psychiatry (Drs Toulopoulou, Picchioni, Hua-Hall, Ettinger, and Murray) and Medical Research Council Social, Genetic, and Developmental Psychiatry Centre (Drs Rijsdijk and Sham), Institute of Psychiatry, King's College London, London, England; and Department of Psychiatry, University of Hong Kong, Hong Kong (Dr Sham).

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