Browsing by Subject "Endophenotypes"

Now showing 1 - 2 of 2

Open Access
Heritability of neuropsychological measures in schizophrenia and nonpsychiatric populations: a systematic review and meta-analysis
(Oxford University Press, 2017) Blokland, G. A. M.; Mesholam-Gately, R. I.; Toulopoulou, T.; Del Re, E. C.; Lam, M.; Delisi, L. E.; Donohoe, G.; Walters, J. T. R.; Seidman, L. J.; Petryshen, T. L.
Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average r g = '.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.
Open Access
Polygenic risk score increases schizophrenia liability through cognition-relevant pathways
(Oxford University Press, 2019) Toulopoulou, Timothea; Zhang, X.; Cherny, S.; Dickinson, D.; Berman, K. F.; Straub, R. E.; Sham, P.; Weinberger, D. R.
Cognitive deficit is thought to represent, at least in part, genetic mechanisms of risk for schizophrenia, with recent evidence from statistical modelling of twin data suggesting direct causality from the former to the latter. However, earlier evidence was based on inferences from twin not molecular genetic data and it is unclear how much genetic influence ‘passes through’ cognition on the way to diagnosis. Thus, we included direct measurements of genetic risk (e.g. schizophrenia polygenic risk scores) in causation models to assess the extent to which cognitive deficit mediates some of the effect of polygenic risk scores on the disorder. Causal models of family data tested relationships among key variables and allowed parsing of genetic variance components. Polygenic risk scores were calculated from summary statistics from the current largest genome-wide association study of schizophrenia and were represented as a latent trait. Cognition was also modelled as a latent trait. Participants were 1313 members of 1078 families: 416 patients with schizophrenia, 290 unaffected siblings, and 607 controls. Modelling supported earlier findings that cognitive deficit has a putatively causal role in schizophrenia. In total, polygenic risk score explained 8.07% [confidence interval (CI) 5.45–10.74%] of schizophrenia risk in our sample. Of this, more than a third (2.71%, CI 2.41–3.85%) of the polygenic risk score influence was mediated through cognition paths, exceeding the direct influence of polygenic risk score on schizophrenia risk (1.43%, CI 0.46–3.08%). The remainder of the polygenic risk score influence (3.93%, CI 2.37–4.48%) reflected reciprocal causation between schizophrenia liability and cognition (e.g. mutual influences in a cyclical manner). Analysis of genetic variance components of schizophrenia liability indicated that 26.87% (CI 21.45–32.57%) was associated with cognition-related pathways not captured by polygenic risk score. The remaining variance in schizophrenia was through pathways other than cognition-related and polygenic risk score. Although our results are based on inference through statistical modelling and do not provide an absolute proof of causality, we find that cognition pathways mediate a significant part of the influence of cumulative genetic risk on schizophrenia. We estimate from our model that 33.51% (CI 27.34–43.82%) of overall genetic risk is mediated through influences on cognition, but this requires further studies and analyses as the genetics of schizophrenia becomes better characterized.