Previous genetic studies on hair morphology focused on the overall morphology of the hair using data collected by self-report or researcher observation. Here, we present the first genome-wide association study (GWAS) of a micro-level quantitative measure of hair curvature. We compare these results to GWAS results obtained using a macro-level classification of observable hair curvature performed in the same sample of twins and siblings of European descent. Observational data were collected by trained observers, while quantitative data were acquired using an Optical Fibre Diameter Analyser (OFDA). The GWAS for both the observational and quantitative measures of hair curvature resulted in genome-wide significant signals at chromosome 1q21.3 close to the trichohyalin (TCHH) gene, previously shown to harbor variants associated with straight hair morphology in Europeans. All genetic variants reaching genome-wide significance for both GWAS (quantitative measure lead single-nucleotide polymorphism [SNP] rs12130862, p = 9.5 × 10–09; observational measure lead SNP rs11803731, p = 2.1 × 10–17) were in moderate to very high linkage disequilibrium (LD) with each other (minimum r2 = .45), indicating they represent the same genetic locus. Conditional analyses confirmed the presence of only one signal associated with each measure at this locus. Results from the quantitative measures reconfirmed the accuracy of observational measures.

Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

This letter reflects on my collaborations with Nick Martin over the past 18 years. Working together we have applied twin-family and statistical genetics methods to examine the genetic architecture and identify genetic variants influencing a range of physical, psychological and social traits. The common thread across much of this work has been the empirical questions: Why are we the way we are and how can this knowledge help us when things go wrong?

The aim of the 25 and Up (25Up) study was to assess a wide range of psychological and behavioral risk factors behind mental illness in a large cohort of Australian twins and their non-twin siblings. Participants had already been studied longitudinally from the age of 12 and most recently in the 19Up study (mean age = 26.1 years, SD = 4.1, range = 20–39). This subsequent wave follows up these twins several years later in life (mean age = 29.7 years, SD = 2.2, range =  22–44). The resulting data set enables additional detailed investigations of genetic pathways underlying psychiatric illnesses in the Brisbane Longitudinal Twin Study (BLTS). Data were collected between 2016 and 2018 from 2540 twins and their non-twin siblings (59% female, including 341 monozygotic complete twin-pairs, 415 dizygotic complete pairs and 1028 non-twin siblings and singletons). Participants were from South-East Queensland, Australia, and the sample was of predominantly European ancestry. The 25Up study collected information on 20 different mental disorders, including depression, anxiety, substance use, psychosis, bipolar and attention-deficit hyper-activity disorder, as well as general demographic information such as occupation, education level, number of children, self-perceived IQ and household environment. In this article, we describe the prevalence, comorbidities and age of onset for all 20 examined disorders. The 25Up study also assessed general and physical health, including physical activity, sleep patterns, eating behaviors, baldness, acne, migraines and allergies, as well as psychosocial items such as suicidality, perceived stress, loneliness, aggression, sleep–wake cycle, sexual identity and preferences, technology and internet use, traumatic life events, gambling and cyberbullying. In addition, 25Up assessed female health traits such as morning sickness, breastfeeding and endometriosis. Furthermore, given that the 25Up study is an extension of previous BLTS studies, 86% of participants have already been genotyped. This rich resource will enable the assessment of epidemiological risk factors, as well as the heritability and genetic correlations of mental conditions.

We recently reported an association of offspring educational attainment with polygenic risk scores (PRS) computed on parent’s non-transmitted alleles for educational attainment using the second GWAS meta-analysis article on educational attainment published by the Social Science Genetic Association Consortium. Here we test the replication of these findings using a more powerful PRS from the third GWAS meta-analysis article by the Consortium. Each of the key findings of our previous paper is replicated using this improved PRS (N = 2335 adolescent twins and their genotyped parents). The association of children’s attainment with their own PRS increased substantially with the standardized effect size, moving from β = 0.134, 95% CI = 0.079, 0.188 for EA2, to β = 0.223, 95% CI = 0.169, 0.278, p < .001, for EA3. Parent’s PRS again predicted the socioeconomic status (SES) they provided to their offspring and increased from β = 0.201, 95% CI = 0.147, 0.256 to β = 0.286, 95% CI = 0.239, 0.333. Importantly, the PRS for alleles not transmitted to their offspring — therefore acting via the parenting environment — was increased in effect size from β = 0.058, 95% CI = 0.003, 0.114 to β = 0.067, 95% CI = 0.012, 0.122, p = .016. As previously found, this non-transmitted genetic effect was fully accounted for by parental SES. The findings reinforce the conclusion that genetic effects of parenting are substantial, explain approximately one-third the magnitude of an individual’s own genetic inheritance and are mediated by parental socioeconomic competence.

Psychological distress (PSYCH), somatic distress (SOMA), affective disorders (AD), and substance use (SU) frequently co-occur. The genetic relationship between PSYCH and SOMA, however, remains understudied. We examined the genetic and environmental influences on these two disorders and their comorbid AD and SU using structural equation modeling. Self-reported PSYCH and SOMA were measured in 1,548 twins using the two subscales of a 12-item questionnaire, the Somatic and Psychological Health Report. Its reliability and psychometric properties were examined. Six ADs, involvement of licit and illicit substance, and two SU disorders were obtained from 1,663–2,132 twins using the World Mental Health Composite International Diagnostic Interview and/or from an online adaption of the same. SU phenotypes (heritability: 49–79%) were found to be more heritable than the affective disorder phenotypes (heritability: 32–42%), SOMA (heritability: 25%), and PSYCH (heritability: 23%). We fit separate non-parametric item response theory models for PSYCH, SOMA, AD, and SU. The IRT scores were used as the refined phenotypes for fitting multivariate genetic models. The best-fitting model showed the similar amount of genetic overlap between PSYCH–AD (genetic correlation rG = 0.49) and SOMA–AD (rG =0.53), as well as between PSYCH–SU (rG = 0.23) and SOMA–SU (rG = 0.25). Unique environmental factors explained 53% to 76% of the variance in each of these four phenotypes, whereas additive genetic factors explained 17% to 46% of the variance. The covariance between the four phenotypes was largely explained by unique environmental factors. Common genetic factor had a significant influence on all the four phenotypes, but they explained a moderate portion of the covariance.

Drinking alcohol is a normal behavior in many societies, and prior studies have demonstrated it has both genetic and environmental sources of variation. Using two very large samples of twins and their first-degree relatives (Australia ≈ 20,000 individuals from 8,019 families; Virginia ≈ 23,000 from 6,042 families), we examine whether there are differences: (1) in the genetic and environmental factors that influence four interrelated drinking behaviors (quantity, frequency, age of initiation, and number of drinks in the last week), (2) between the twin-only design and the extended twin design, and (3) the Australian and Virginia samples. We find that while drinking behaviors are interrelated, there are substantial differences in the genetic and environmental architectures across phenotypes. Specifically, drinking quantity, frequency, and number of drinks in the past week have large broad genetic variance components, and smaller but significant environmental variance components, while age of onset is driven exclusively by environmental factors. Further, the twin-only design and the extended twin design come to similar conclusions regarding broad-sense heritability and environmental transmission, but the extended twin models provide a more nuanced perspective. Finally, we find a high level of similarity between the Australian and Virginian samples, especially for the genetic factors. The observed differences, when present, tend to be at the environmental level. Implications for the extended twin model and future directions are discussed.

Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.

Acne vulgaris is a skin disease with a multifactorial and complex pathology. While several twin studies have estimated that acne has a heritability of up to 80%, the genomic elements responsible for the origin and pathology of acne are still undiscovered. Here we performed a twin-based structural equation model, using available data on acne severity for an Australian sample of 4,491 twins and their siblings aged from 10 to 24. This study extends by a factor of 3 an earlier analysis of the genetic factors of acne. Acne severity was rated by nurses on a 4-point scale (1 = absent to 4 = severe) on up to three body sites (face, back, chest) and on up to three occasions (age 12, 14, and 16). The phenotype that we analyzed was the most severe rating at any site or age. The polychoric correlation for monozygotic twins was higher (rMZ = 0.86, 95% CI [0.81, 0.90]) than for dizygotic twins (rDZ = 0.42, 95% CI [0.35, 0.47]). A model that includes additive genetic effects and unique environmental effects was the most parsimonious model to explain the genetic variance of acne severity, and the estimated heritability was 0.85 (95% CI [0.82, 0.87]). We then conducted a genome-wide analysis including an additional 271 siblings — for a total of 4,762 individuals. A genome-wide association study (GWAS) scan did not detect loci associated with the severity of acne at the threshold of 5E-08 but suggestive association was found for three SNPs: rs10515088 locus 5q13.1 (p = 3.9E-07), rs12738078 locus 1p35.5 (p = 6.7E-07), and rs117943429 locus 18q21.2 (p = 9.1E-07). The 5q13.1 locus is close to PIK3R1, a gene that has a potential regulatory effect on sebocyte differentiation.

Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.

Neuroticism, a ‘Big Five’ personality trait, has been associated with sub-clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (r g = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD.

Hair diameter and curvature are two characteristics of human scalp hair used in forensic contexts. While previous data show that subjective categorization of hair curvature is highly heritable, the heritability of objectively measured curvature and diameter, and variability of hair characteristics within each individual have not yet been studied. The present study measured hair diameter and curvature using an optical fiber diameter analyzer in a sample of 2,332 twins and siblings. Heritability was estimated using maximum likelihood structural equation modeling. Results show sex differences in the magnitude of genetic influence for mean diameter and curvature, with the vast majority of the variance accounted for by genetic effects in males (diameter = 86%, curvature = 53%) and females (diameter = 77%, curvature = 61%). The consistency of diameter (variance within an individual) was also highly heritable, but did not show sex limitation, with 68% of the variance accounted for by genetic factors. Moderate phenotypic correlations were seen between diameter and consistency (r = 0.3) but there was little correlation between diameter and curvature (r = -0.13). A bivariate Cholesky analysis was used to estimate the genetic and environmental correlations between hair diameter and consistency, yielding genetic correlations of rgF = 0.27 for females and rgM = 0.25 for males.

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.