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It is widely recognized that dizygotic twinning (DZT) runs in families, but estimates of heritability from twin and family data are remarkably scarce and vary considerably. Here, we traced seven large, sometimes historical, multigeneration pedigrees from West Africans, fin de siècle French Jews, Canadians (two pedigrees), and the French royal family, in which twin births were recorded. We estimated heritability of twinning (of all types) as zygosity information was not available, diluting the true DZT heritability by a third or so. The estimates in the range 8−20% are remarkably consistent across time (8−19 generations) and ethnicities and also consistent with twin and family estimates.
Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.
Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.
Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.
Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
Previous research has shown that self-reports of the amount of social support are heritable. Using the Kessler perceived social support (KPSS) measure, we explored sex differences in the genetic and environmental contributions to individual differences. We did this separately for subscales that captured the perceived support from different members of the network (spouse, twin, children, parents, relatives, friends and confidant). Our sample comprised 7059 male, female and opposite-sex twin pairs aged 18−95 years from the Australian Twin Registry. We found tentative support for different genetic mechanisms in males and females for support from friends and the average KPSS score of all subscales, but otherwise, there are no sex differences. For each subscale alone, the additive genetic (A) and unique environment (E) effects were significant. By contrast, the covariation among the subscales was explained — in roughly equal parts — by A, E and the common environment, with effects of different support constellations plausibly accounting for the latter. A single genetic and common environment factor accounted for between half and three-quarters of the variance across the subscales in both males and females, suggesting little heterogeneity in the genetic and environmental etiology of the different support sources.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.
Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e−8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p < .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the associations in chromosomes 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.
Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41–200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson’s disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.
A paleontological deposit near San Clemente de Térapa represents one of the very few Rancholabrean North American Land Mammal Age sites within Sonora, Mexico. During that time, grasslands were common, and the climate included cooler and drier summers and wetter winters than currently experienced in northern Mexico. Here, we demonstrate restructuring in the mammalian community associated with environmental change over the past 40,000 years at Térapa. The fossil community has a similar number of carnivores and herbivores whereas the modern community consists mostly of carnivores. There was also a 97% decrease in mean body size (from 289 kg to 9 kg) because of the loss of megafauna. We further provide an updated review of ungulates and carnivores, recognizing two distinct morphotypes of Equus, including E. scotti and a slighter species; as well as Platygonus compressus; Camelops hesternus; Canis dirus; and Lynx rufus; and the first regional records of Palaeolama mirifica, Procyon lotor, and Smilodon cf. S. fatalis. The Térapa mammals presented here provide a more comprehensive understanding of the faunal community restructuring that occurred in northern Mexico from the late Pleistocene to present day, indicating further potential biodiversity loss with continued warming and drying of the region.
Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue.
A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types.
Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use.
Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.
The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.
The ‘16Up’ study conducted at the QIMR Berghofer Medical Research Institute from January 2014 to December 2018 aimed to examine the physical and mental health of young Australian twins aged 16−18 years (N = 876; 371 twin pairs and 18 triplet sets). Measurements included online questionnaires covering physical and mental health as well as information and communication technology (ICT) use, actigraphy, sleep diaries and hair samples to determine cortisol concentrations. Study participants generally rated themselves as being in good physical (79%) and mental (73%) health and reported lower rates of psychological distress and exposure to alcohol, tobacco products or other substances than previously reported for this age group in the Australian population. Daily or near-daily online activity was almost universal among study participants, with no differences noted between males and females in terms of frequency or duration of internet access. Patterns of ICT use in this sample indicated that the respondents were more likely to use online information sources for researching physical health issues than for mental health or substance use issues, and that they generally reported partial levels of satisfaction with the mental health information they found online. This suggests that internet-based mental health resources can be readily accessed by adolescent Australians, and their computer literacy augurs well for future access to online health resources. In combination with other data collected as part of the ongoing Brisbane Longitudinal Twin Study, the 16Up project provides a valuable resource for the longitudinal investigation of genetic and environmental contributions to phenotypic variation in a variety of human traits.
Mortality risk is known to be associated with many physiological or biochemical risk factors, and polygenic risk scores (PRSs) may offer an additional or alternative approach to risk stratification. We have compared the predictive value of common biochemical tests, PRSs and information on parental survival in a cohort of twins and their families. Common biochemical test results were available for up to 13,365 apparently healthy men and women, aged 17−93 years (mean 49.0, standard deviation [SD] 13.7) at blood collection. PRSs for longevity were available for 14,169 study participants and reported parental survival for 25,784 participants. A search for information on date and cause of death was conducted through the Australian National Death Index, with median follow-up of 11.3 years. Cox regression was used to evaluate associations with mortality from all causes, cancers, cardiovascular diseases and other causes. Linear relationships with all-cause mortality were strongest for C-reactive protein, gamma-glutamyl transferase, glucose and alkaline phosphatase, with hazard ratios (HRs) of 1.16 (95% CI [1.07, 1.24]), 1.15 (95% CI 1.04–1.21), 1.13 (95% CI [1.08, 1.19]) and 1.11 (95% CI [1.05, 1.88]) per SD difference, respectively. Significant nonlinear effects were found for urea, uric acid and butyrylcholinesterase. Lipid risk factors were not statistically significant for mortality in our cohort. Family history and PRS showed weaker but significant associations with survival, with HR in the range 1.05 to 1.09 per SD difference. In conclusion, biochemical tests currently predict long-term mortality more strongly than genetic scores based on genotyping or on reported parental survival.
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.
Antarctica's ice shelves modulate the grounded ice flow, and weakening of ice shelves due to climate forcing will decrease their ‘buttressing’ effect, causing a response in the grounded ice. While the processes governing ice-shelf weakening are complex, uncertainties in the response of the grounded ice sheet are also difficult to assess. The Antarctic BUttressing Model Intercomparison Project (ABUMIP) compares ice-sheet model responses to decrease in buttressing by investigating the ‘end-member’ scenario of total and sustained loss of ice shelves. Although unrealistic, this scenario enables gauging the sensitivity of an ensemble of 15 ice-sheet models to a total loss of buttressing, hence exhibiting the full potential of marine ice-sheet instability. All models predict that this scenario leads to multi-metre (1–12 m) sea-level rise over 500 years from present day. West Antarctic ice sheet collapse alone leads to a 1.91–5.08 m sea-level rise due to the marine ice-sheet instability. Mass loss rates are a strong function of the sliding/friction law, with plastic laws cause a further destabilization of the Aurora and Wilkes Subglacial Basins, East Antarctica. Improvements to marine ice-sheet models have greatly reduced variability between modelled ice-sheet responses to extreme ice-shelf loss, e.g. compared to the SeaRISE assessments.
Despite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG.
Participants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates.
Neither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality.
These findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.
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.
Loneliness is related to mental and somatic health outcomes, including borderline personality disorder. Here, we analyze the sources of variation that are responsible for the relationship between borderline personality features (including four dimensions, affective instability, identity disturbance, negative relationships, self-harm and a total score) and loneliness. Using genetically informative data from two large nonclinical samples of adult twin pairs from Australia and the Netherlands (N = 11,329), we estimate the phenotypic, genetic and environmental correlations between self-reported borderline personality features and loneliness. Individual differences in borderline personality and loneliness were best explained by additive genetic factors with heritability estimates h2 = 41% for the borderline personality total score and h2 = 36% for loneliness, with the remaining variation explained by environmental influences that were not shared by twins from the same pair. Genetic and environmental factors influencing borderline personality (total score and four subscales separately) were also partial causes of loneliness. The correlation between loneliness and the borderline personality total score was rph = .51. The genetic correlation was estimated at rg = .64 and the environmental correlation at re = .40. Our study suggests common etiological factors in loneliness and borderline personality features.
Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7–73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.
Here we provide an update of the 2013 report on the Nigerian Twin and Sibling Registry (NTSR). The major aim of the NTSR is to understand genetic and environmental influences and their interplay in psychological and mental health development in Nigerian children and adolescents. Africans have the highest twin birth rates among all human populations, and Nigeria is the most populous country in Africa. Due to its combination of large population and high twin birth rates, Nigeria has one of the largest twin populations in the world. In this article, we provide current updates on the NTSR samples recruited, recruitment procedures, zygosity assessment and findings emerging from the NTSR.