GWIS: Genome-Wide Inferred Statistics for Functions of Multiple Phenotypes.

Here we present a method of genome-wide inferred study (GWIS) that provides an approximation of genome-wide association study (GWAS) summary statistics for a variable that is a function of phenotypes for which GWAS summary statistics, phenotypic means, and covariances are available. A GWIS can be performed regardless of sample overlap between the GWAS of the phenotypes on which the function depends. Because a GWIS provides association estimates and their standard errors for each SNP, a GWIS can form the basis for polygenic risk scoring, LD score regression, Mendelian randomization studies, biological annotation, and other analyses. GWISs can also be used to boost power of a GWAS meta-analysis where cohorts have not measured all constituent phenotypes in the function. We demonstrate the accuracy of a BMI GWIS by performing power simulations and type I error simulations under varying circumstances, and we apply a GWIS by reconstructing a body mass index (BMI) GWAS based on a weight GWAS and a height GWAS. Furthermore, we apply a GWIS to further our understanding of the underlying genetic structure of bipolar disorder and schizophrenia and their relation to educational attainment. Our analyses suggest that the previously reported genetic correlation between schizophrenia and educational attainment is probably induced by the observed genetic correlation between schizophrenia and bipolar disorder and the previously reported genetic correlation between bipolar disorder and educational attainment.

An Extended Twin-Pedigree Study of Neuroticism in the Netherlands Twin Register.

For the participants in the Netherlands Twin Register (NTR) we constructed the extended pedigrees which specify all relations among nuclear and larger twin families in the register. A total of 253,015 subjects from 58,645 families were linked to each other, to the degree that we had information on the relations among participants. We describe the algorithm that was applied to construct the pedigrees. For > 30,000 adolescent and adult NTR participants data were available on harmonized neuroticism scores. We analyzed these data in the Mendel software package (Lange et al., Bioinformatics 29(12):1568-1570, 2013) to estimate the contributions of additive and non-additive genetic factors. In contrast to much of the earlier work based on twin data rather than on extended pedigrees, we could also estimate the contribution of shared household effects in the presence of non-additive genetic factors. The estimated broad-sense heritability of neuroticism was 47%, with almost equal contributions of additive and non-additive (dominance) genetic factors. A shared household effect explained 13% and unique environmental factors explained the remaining 40% of the variance in neuroticism.

The Computerized Neurocognitive Battery: Validation, aging effects, and heritability across cognitive domains.

OBJECTIVE: The Computerized Neurocognitive Battery (CNB) enables efficient neurocognitive assessment. The authors aimed to (a) estimate validity and reliability of the battery's Dutch translation, (b) investigate effects of age across cognitive domains, and (c) estimate heritability of the CNB tests. METHOD: A population-representative sample of 1,140 participants (aged 10-86), mainly twin-families, was tested on the CNB, providing measures of speed and accuracy in 14 cognitive domains. In a subsample (246 subjects aged 14-22), IQ data (Wechsler Intelligence Scale for Adults; WAIS) were available. Validity and reliability were assessed by Cronbach's alpha, comparisons of scores between Dutch and U.S. samples, and investigation of how a CNB-based common factor compared to a WAIS-based general factor of intelligence (g). Linear and nonlinear age dependencies covering the life span were modeled through regression. Heritability was estimated from twin data and from entire pedigree data. RESULTS: Internal consistency of all tests was moderate to high (median = 0.86). Effects of gender, age, and education on cognitive performance closely resembled U.S. SAMPLES: The CNB-based common factor was completely captured by the WAIS-based g. Some domains, like nonverbal reasoning accuracy, peaked in young adulthood and showed steady decline. Other domains, like language reasoning accuracy, peaked in middle adulthood and were spared decline. CNB-test heritabilities were moderate (median h2 = 31%). Heritability of the CNB common factor was 70%, similar to the WAIS-based g-factor. CONCLUSION: The CNB can be used to assess specific neurocognitive performance, as well as to obtain a reliable proxy of general intelligence. Effects of aging and heritability differed across cognitive domains.