Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood

The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, QLD 4102 and Department of Agriculture and Food Systems, University of Melbourne, VIC 3010, Melbourne, Australia.
Bioinformatics (Impact Factor: 4.62). 07/2012; 28(19):2540-2. DOI: 10.1093/bioinformatics/bts474
Source: PubMed

ABSTRACT Genetic correlations are the genome-wide aggregate effects of causal variants affecting multiple traits. Traditionally, genetic correlations between complex traits are estimated from pedigree studies, but such estimates can be confounded by shared environmental factors. Moreover, for diseases, low prevalence rates imply that even if the true genetic correlation between disorders was high, co-aggregation of disorders in families might not occur or could not be distinguished from chance. We have developed and implemented statistical methods based on linear mixed models to obtain unbiased estimates of the genetic correlation between pairs of quantitative traits or pairs of binary traits of complex diseases using population-based case-control studies with genome-wide single-nucleotide polymorphism data. The method is validated in a simulation study and applied to estimate genetic correlation between various diseases from Wellcome Trust Case Control Consortium data in a series of bivariate analyses. We estimate a significant positive genetic correlation between risk of Type 2 diabetes and hypertension of ~0.31 (SE 0.14, P = 0.024).
Our methods, appropriate for both quantitative and binary traits, are implemented in the freely available software GCTA ( Supplementary Information: Supplementary data are available at Bioinformatics online.

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    • "We also used bivariate GCTA (Lee et al. 2012) to estimate the extent to which the same genes contribute to the observed phenotypic correlation between two variables. These estimations are based on the genetic covariance between untransformed peer problem measures at different ages, which is due to common measured genetic variation. "
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    ABSTRACT: Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population-based birth-cohort (ALSPAC, 4-17 years), and a UK twin sample (TEDS, 4-11 years). Longitudinal twin analysis (TEDS; N ≤ 7,366 twin pairs) showed that peer problems in childhood are heritable (4-11 years, 0.60 < twin-h (2) ≤ 0.71) but genetically heterogeneous from age to age (4-11 years, twin-r g = 0.30). N ≤ 5,608, TEDS: N ≤ 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4-12 years, 0.02<[Formula: see text] ≤ 0.11) though these influences become stronger in adolescence (13-17 years, 0.14<[Formula: see text] ≤ 0.27). A subsequent cross-sectional genome-wide screen in ALSPAC (N ≤ 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA-P ≤ 0.03). Single variant signals (P ≤ 10(-5)) were followed up in TEDS (N ≤ 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N Pedigrees = 793; ACC: N Cases = 1,453/N Controls = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence.
    Human Genetics 12/2014; 134(6). DOI:10.1007/s00439-014-1514-5 · 4.52 Impact Factor
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    • "Some research (Conley et al., 2014) suggests that GCTA results may be robust to violations of this assumption, but more work in this area is needed. This univariate GCTA model has been recently extended to a bivariate specification in which the same genetic relationship can be used to examine covariance between two traits as a function of genetic similarity (Lee et al., 2012). The model is derived from twin-sibling approaches in which cross-twin-cross-trait covariance is compared among monozygotic and dizygotic twin pairs to see if there is evidence that the covariance is due to common genetic influences. "
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    ABSTRACT: We use genome wide data from respondents of the Health and Retirement Study (HRS) to evaluate the possibility that common genetic influences are associated with education and three health outcomes: depression, self-rated health, and body mass index. We use a total of 1.7 million single nucleotide polymorphisms obtained from the Illumina HumanOmni2.5-4v1 chip from 4233 non-Hispanic white respondents to characterize genetic similarities among unrelated persons in the HRS. We then used the Genome Wide Complex Trait Analysis (GCTA) toolkit, to estimate univariate and bivariate heritability. We provide evidence that education (h(2) = 0.33), BMI (h(2) = 0.43), depression (h(2) = 0.19), and self-rated health (h(2) = 0.18) are all moderately heritable phenotypes. We also provide evidence that some of the correlation between depression and education as well as self-rated health and education is due to common genetic factors associated with one or both traits. We find no evidence that the correlation between education and BMI is influenced by common genetic factors.
    Social Science & Medicine 08/2014; 127. DOI:10.1016/j.socscimed.2014.08.001 · 2.56 Impact Factor
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    • "However, our hypothesis for an association between loci associated with schizophrenia and adolescent psychotic experiences is supported by phenotypic associations reported between earlier psychotic experiences and adult psychosis [4],[5]. Fifth, the genetic correlation between adolescent psychotic experiences and adult schizophrenia is not known because no twin data or genome-wide complex trait analysis (GCTA) [40],[41] findings on this bivariate relationship have been reported. It is not known the degree to which the relationship between adolescent psychotic experiences and psychotic disorders is influenced by genetic or environmental influences. "
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    ABSTRACT: Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value = 2.57×10-4) and rs9960767 (p-value = 6.23×10-4). Replication in an independent sample of 16-year-olds (N = 3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed.
    PLoS ONE 04/2014; 9(4):e94398. DOI:10.1371/journal.pone.0094398 · 3.23 Impact Factor
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