Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship (Formula: see text) among 417,060 ...individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and Formula: see text that agree with the SNP-based heritability (Formula: see text) in unrelated pairs (Formula: see text), and with pedigree-estimated heritability in close relatives (Formula: see text). The covariance increases faster than Formula: see text in distant relatives (Formula: see text), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct Formula: see text. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.
Human DNA polymorphisms vary across geographic regions, with the most commonly observed variation reflecting distant ancestry differences. Here we investigate the geographic clustering of common ...genetic variants that influence complex traits in a sample of ~450,000 individuals from Great Britain. Of 33 traits analysed, 21 showed significant geographic clustering at the genetic level after controlling for ancestry, probably reflecting migration driven by socioeconomic status (SES). Alleles associated with educational attainment (EA) showed the most clustering, with EA-decreasing alleles clustering in lower SES areas such as coal mining areas. Individuals who leave coal mining areas carry more EA-increasing alleles on average than those in the rest of Great Britain. The level of geographic clustering is correlated with genetic associations between complex traits and regional measures of SES, health and cultural outcomes. Our results are consistent with the hypothesis that social stratification leaves visible marks in geographic arrangements of common allele frequencies and gene-environment correlations.
Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association ...studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.
Research on gene × environment interaction in major depressive disorder (MDD) has thus far primarily focused on candidate genes, although genetic effects are known to be polygenic.
To test whether ...the effect of polygenic risk scores on MDD is moderated by childhood trauma.
The study sample consisted of 1645 participants with a DSM-IV diagnosis of MDD and 340 screened controls from The Netherlands. Chronic or remitted episodes (severe MDD) were present in 956 participants. The occurrence of childhood trauma was assessed with the Childhood Trauma Interview and the polygenic risk scores were based on genome-wide meta-analysis results from the Psychiatric Genomics Consortium.
The polygenic risk scores and childhood trauma independently affected MDD risk, and evidence was found for interaction as departure from both multiplicativity and additivity, indicating that the effect of polygenic risk scores on depression is increased in the presence of childhood trauma. The interaction effects were similar in predicting all MDD risk and severe MDD risk, and explained a proportion of variation in MDD risk comparable to the polygenic risk scores themselves.
The interaction effect found between polygenic risk scores and childhood trauma implies that (1) studies on direct genetic effect on MDD gain power by focusing on individuals exposed to childhood trauma, and that (2) individuals with both high polygenic risk scores and exposure to childhood trauma are particularly at risk for developing MDD.
We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both ...Icelandic (P = 5.2 × 10(-6) and 3.8 × 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.
Genome-wide association studies on human behavioural traits are producing large amounts of polygenic signals with significant predictive power and potentially useful biological clues. Behavioural ...traits are more distal and are less directly under biological control compared with physical characteristics, which makes the associated genetic effects harder to interpret. The results of genome-wide association studies for human behaviour are likely made up of a composite of signals from different sources. While sample sizes continue to increase, we outline additional steps that need to be taken to better delineate the origin of the increasingly stronger polygenic signals. In addition to genetic effects on the traits themselves, the major sources of polygenic signals are those that are associated with correlated traits, environmental effects and ascertainment bias. Advances in statistical approaches that disentangle polygenic effects from different traits as well as extending data collection to families and social circles with better geographical coverage will probably contribute to filling the gap of knowledge between genetic effects and behavioural outcomes.
Background and Aims
Loneliness is associated with cigarette smoking and problematic alcohol use. Observational evidence suggests these associations arise because loneliness increases substance use; ...however, there is potential for reverse causation (problematic drinking damages social networks, leading to loneliness). With conventional epidemiological methods, controlling for (residual) confounding and reverse causality is difficult. This study applied Mendelian randomization (MR) to assess bidirectional causal effects among loneliness, smoking behaviour and alcohol (mis)use. MR uses genetic variants as instrumental variables to estimate the causal effect of an exposure on an outcome, if the assumptions are satisfied.
Design
Our primary method was inverse‐variance weighted (IVW) regression and the robustness of these findings was assessed with five different sensitivity methods.
Setting
European ancestry.
Participants
Summary‐level data were drawn from the largest available independent genome‐wide association studies (GWAS) of loneliness (n = 511 280), smoking (initiation (n = 249 171), cigarettes per day (n = 249 171) and cessation (n = 143 852), alcoholic drinks per week (n = 226 223) and alcohol dependence (n = 46 568).
Measurements
Genetic variants predictive of the exposure variable were selected as instruments from the respective GWAS.
Findings
There was weak evidence of increased loneliness leading to higher likelihood of initiating smoking, smoking more cigarettes, and a lower likelihood of quitting smoking. Additionally, there was evidence that initiating smoking increases loneliness IVW, β = 0.30, 95% confidence interval (CI) = 0.22–0.38, P = 2.8 × 10−13. We found no clear evidence for a causal effect of loneliness on drinks per week (IVW, β = 0.01, 95% CI = −0.11, 0.13, P = 0.865) or alcohol dependence (IVW, β = 0.09, 95% CI = −0.19, 0.36, P = 0.533) nor of alcohol use on loneliness (drinks per week IVW, β = 0.09, 95% CI = −0.02, 0.22, P = 0.076; alcohol dependence IVW, β = 0.06, 95% CI = −0.02, 0.13, P = 0.162).
Conclusions
There appears to be tentative evidence for causal, bidirectional, increasing effects between loneliness and cigarette smoking, especially for smoking initiation increasing loneliness.
Genetic differences between individuals underlie susceptibility to many diseases. Genome-wide association studies (GWAS) have discovered many susceptibility genes but were often limited to cohorts of ...predominantly European ancestry. Genetic diversity between individuals due to different ancestries and evolutionary histories shows that this approach has limitations. In order to gain a better understanding of the associated genetic variation, we need a more global genomics approach including a greater diversity. Here, we introduce the Healthy Life in an Urban Setting (HELIUS) cohort. The HELIUS cohort consists of participants living in Amsterdam, with a level of diversity that reflects the Dutch colonial and recent migration past. The current study includes 10,283 participants with genetic data available from seven groups of inhabitants, namely, Dutch, African Surinamese, South-Asian Surinamese, Turkish, Moroccan, Ghanaian, and Javanese Surinamese. First, we describe the genetic variation and admixture within the HELIUS cohort. Second, we show the challenges during imputation when having a genetically diverse cohort. Third, we conduct a body mass index (BMI) and height GWAS where we investigate the effects of a joint analysis of the entire cohort and a meta-analysis approach for the different subgroups. Finally, we construct polygenic scores for BMI and height and compare their predictive power across the different ethnic groups. Overall, we give a comprehensive overview of a genetically diverse cohort from Amsterdam. Our study emphasizes the importance of a less biased and more realistic representation of urban populations for mapping genetic associations with complex traits and disease risk for all.
We assessed gene expression profiles in 2,752 twins, using a classic twin design to quantify expression heritability and quantitative trait loci (eQTLs) in peripheral blood. The most highly heritable ...genes (∼777) were grouped into distinct expression clusters, enriched in gene-poor regions, associated with specific gene function or ontology classes, and strongly associated with disease designation. The design enabled a comparison of twin-based heritability to estimates based on dizygotic identity-by-descent sharing and distant genetic relatedness. Consideration of sampling variation suggests that previous heritability estimates have been upwardly biased. Genotyping of 2,494 twins enabled powerful identification of eQTLs, which we further examined in a replication set of 1,895 unrelated subjects. A large number of non-redundant local eQTLs (6,756) met replication criteria, whereas a relatively small number of distant eQTLs (165) met quality control and replication standards. Our results provide a new resource toward understanding the genetic control of transcription.
Understanding how parents' cognitive and non-cognitive skills influence offspring education is essential for educational, family and economic policy. We use genetics (GWAS-by-subtraction) to assess a ...latent, broad non-cognitive skills dimension. To index parental effects controlling for genetic transmission, we estimate indirect parental genetic effects of polygenic scores on childhood and adulthood educational outcomes, using siblings (N = 47,459), adoptees (N = 6407), and parent-offspring trios (N = 2534) in three UK and Dutch cohorts. We find that parental cognitive and non-cognitive skills affect offspring education through their environment: on average across cohorts and designs, indirect genetic effects explain 36-40% of population polygenic score associations. However, indirect genetic effects are lower for achievement in the Dutch cohort, and for the adoption design. We identify potential causes of higher sibling- and trio-based estimates: prenatal indirect genetic effects, population stratification, and assortative mating. Our phenotype-agnostic, genetically sensitive approach has established overall environmental effects of parents' skills, facilitating future mechanistic work.
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