Andrew C. Heath

Common SNPs explain a large proportion of the heritability for human height

SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.

Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits

We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.

Testing structural equation models for twin data using LISREL

Simple genetic models can be fitted to twin data using software packages such as LISREL (Jöreskog and Sörbom, 1986a). After discussion of data preparation and routine checks on possible violation of assumptions of the twin method, we illustrate univariate, bivariate, and multivariate genetic models which can be tested in cross-sectional twin data using LISREL. These include models for cohort or cohabitation effects, genotype x sex interaction, and certain types of genotype x environment interaction and genotype-environment correlation.

Early sexual abuse and lifetime psychopathology: a co-twin-control study

BACKGROUNDnThis study was designed to determine lifetime prevalence of psychiatric disorders among twins who reported childhood sexual abuse (CSA), and to compare these rates with those among non-abused co-twins. The contribution of familial and individual-specific factors to reported sexual abuse was also examined.nnnMETHODnInformation about lifetime psychopathology and substance use was obtained by structured telephone interviews with 5995 Australian twins. Twins who reported a history of childhood sexual abuse (CSA) were contrasted on lifetime psychopathology with subjects without such a history; in addition, comparisons were made between same-sex twin pairs discordant for CSA.nnnRESULTSnA history of CSA was reported by 5.9% of the women and 2.5% of the men. In the sample as a whole, those reporting CSA were more likely to receive lifetime diagnoses of major depression, conduct disorder, panic disorder and alcoholism, and were more likely to report suicidal ideation and a history of suicide attempt. Abused women, but not men, were also more likely to report social phobia. When comparisons were restricted to non-abused co-twins, no differences in psychopathology were seen. However, rates of major depression, conduct disorder and suicidal ideation were higher if both co-twins were abused than if the respondent alone reported CSA. Model-fitting indicated that shared environmental factors influenced risk for reported CSA in women, but not in men.nnnCONCLUSIONnThe association between CSA and psychopathology arises at least in part through the influence of shared familial factors on both risk of victimization and risk of psychopathology.

The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression

BACKGROUNDnSerotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression.nnnMETHODnWe typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype.nnnRESULTSnThere were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype x stressful life event interaction.nnnCONCLUSIONSnRegardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression, Only 20 % of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.

Genome-wide meta-analysis identifies new susceptibility loci for migraine

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10−8). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Genetic and Environmental Structure of the Tridimensional Personality Questionnaire: Three or Four Temperament Dimensions?

Previous phenotypic factor analyses suggest that C. R. Cloningers Tridimensional Personality Questionnaire (TPQ; 1987c) assesses 4 rather than 3 temperament dimensions. The purpose of this study was to determine whether Cloningers revised 4-factor model showed incremental validity over his original model and to investigate the convergent and discriminant validity of Cloningers dimensions in comparison to the personality dimensions proposed by H. J. Eysenck (1981) and J. A. Gray (1970). The sample included 2,420 women and 870 men (aged 50-96) from a volunteer population-based sample of twins. Joint phenotypic factor analyses supported Cloningers 4-dimensional temperament model. A 4-dimensional genetical factor structure was also confirmed in genetic analyses of the TPQ higher order dimensions in women. For men only 3 genetic factors were necessary to explain the genetic variance among the TPQ dimensions.

A theory of developmental change in quantitative phenotypes applied to cognitive development.

A model is presented for the changes in familial resemblance as a function of age. The model allows for separate developmental components of genetic and environmental effects and for the influence of earlier phenotypic values on current measurements. Genetic and environmental effects may be specific to occasions or constant over time. Expected covariances are derived within individuals and between relatives measured at different ages. Parameter substitution shows that models with different assumptions about the mechanism of development yield different predictions for temporal changes in family resemblance. The application of the model is illustrated by the analysis of published longitudinal data on cognitive development. The data suggest that the continuity of cognitive performance over time and the increase in heritability with age reflect the cumulative long-term effects of a single set of genes expressed throughout development. The quality of the shared environment changes from family to family over time but appears to exercise a long-term effect on cognitive development.

Major depression and phobias: the genetic and environmental sources of comorbidity

In a population based sample of 2163 personally interviewed female twins, substantial comorbidity was observed between DSM-III-R defined major depression (MD) and 4 subtypes of phobia: agoraphobia, social phobia, animal phobia and situational phobia. However, the level of comorbidity of MD with agoraphobia was much greater than that found with the other phobic subtypes. We concluded bivariate twin analyses to decompose the genetic and environmental sources of comorbidity between MD and the phobias. Our results suggest that a modest proportion of the genetic vulnerability to MD also influences the risk for all phobic subtypes, with the possible exception of situational phobias. Furthermore, the magnitude of comorbidity resulting from this shared genetic vulnerability is similar across the phobic subtypes. By contrast, the non-familial environmental experiences which predispose to depression substantially increase the vulnerability to agoraphobia, have a modest impact on the risk for social and situational phobias and no effect on the risk for animal phobias. The increased comorbidity between MD and agoraphobia results, nearly entirely, from individual-specific environmental risk factors for MD which also increase the risk for agoraphobia but not for other phobias.

The resolution of cultural and biological inheritance: informativeness of different relationships

The informativeness of different relationships for resolving the genetic and cultural transmission of a continuous variable is explored by computer simulation. Extended twin, extended nuclear-family, and adoption designs are considered. Combining data on twin and parent-offspring pairs provides a powerful means of detecting genetic and cultural transmission. The addition of uncle-nephew and first-cousin data sometimes leads to an increase in power. Designs involving monozygotic twin pairs and their offspring are weaker. The most powerful adoption designs involve data on both biological parent-adopted-away offspring and adoptive parent-adopted offspring pairs. In the absence of information about biological parents, combining nuclear-family, adoptive parent-adopted offspring, and adoptive/natural sibling relationships still provides a powerful strategy for hypothesis testing. Adoption designs are more robust than extended twin and extended nuclear-family designs for resolving cultural and biological inheritance in the presence of genetic dominance or phenotypic assortative mating.