ABSTRACT
The "Reading the Mind in the Eyes" Test (Eyes Test) is a widely used assessment of "theory of mind." The NIMH Research Domain Criteria recommends it as one of two tests for "understanding mental states." Previous studies have demonstrated an on-average female advantage on the Eyes Test. However, it is unknown whether this female advantage exists across the lifespan and across a large number of countries. Thus, we tested sex and age differences using the English version of the Eyes Test in adolescents and adults across 57 countries. We also tested for associations with sociodemographic and cognitive/personality factors. We leveraged one discovery dataset (N = 305,726) and three validation datasets (Ns = 642; 5,284; and 1,087). The results show that: i) there is a replicable on-average female advantage in performance on the Eyes Test; ii) performance increases through adolescence and shallowly declines across adulthood; iii) the on-average female advantage is evident across the lifespan; iv) there is a significant on-average female advantage in 36 out of 57 countries; v) there is a significant on-average female advantage on translated (non-English) versions of the Eyes Test in 12 out of 16 countries, as confirmed by a systematic review; vi) D-scores, or empathizing-systemizing, predict Eyes Test performance above and beyond sex differences; and vii) the female advantage is negatively linked to "prosperity" and "autonomy," and positively linked to "collectivism," as confirmed by exploratory country-level analyses. We conclude that the on-average female advantage on the Eyes Test is observed across ages and most countries.
Subject(s)
Eye , Sex Characteristics , Adult , Adolescent , Humans , Male , Female , EmpathyABSTRACT
Autism is a highly heritable, heterogeneous, neurodevelopmental condition. Large-scale genetic studies, predominantly focussing on simplex families and clinical diagnoses of autism have identified hundreds of genes associated with autism. Yet, the contribution of these classes of genes to multiplex families and autistic traits still warrants investigation. Here, we conducted whole-genome sequencing of 21 highly multiplex autism families, with at least three autistic individuals in each family, to prioritise genes associated with autism. Using a combination of both autistic traits and clinical diagnosis of autism, we identify rare variants in genes associated with autism, and related neurodevelopmental conditions in multiple families. We identify a modest excess of these variants in autistic individuals compared to individuals without an autism diagnosis. Finally, we identify a convergence of the genes identified in molecular pathways related to development and neurogenesis. In sum, our analysis provides initial evidence to demonstrate the value of integrating autism diagnosis and autistic traits to prioritise genes.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Neurodevelopmental Disorders , Humans , Autistic Disorder/diagnosis , Autistic Disorder/genetics , Phenotype , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/geneticsABSTRACT
Higher educational attainment is observationally associated with lower risk of Alzheimer's disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer's disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes and Alzheimer's disease. Summary statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer's disease (35 274 cases, 59 163 controls) and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer's disease; (ii) educational attainment and imaging-derived phenotypes; and (iii) imaging-derived phenotypes and Alzheimer's disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer's disease risk. Genetically proxied educational attainment was inversely associated with Alzheimer's disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95% confidence interval 0.60, 0.80). There were positive associations between genetically predicted educational attainment and four cortical metrics (standard deviation units change in imaging phenotype per one standard deviation increase in genetically predicted years of schooling): surface area 0.30 (95% confidence interval 0.20, 0.40); volume 0.29 (95% confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95% confidence interval 0.11, 0.25); local gyrification index 0.21 (95% confidence interval 0.11, 0.31)]; and inverse associations with cortical intracellular volume fraction [-0.09 (95% confidence interval -0.15, -0.03)] and white matter hyperintensities volume [-0.14 (95% confidence interval -0.23, -0.05)]. Genetically proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with educational attainment [standard deviation units change in years of schooling per one standard deviation increase in respective genetically predicted imaging phenotype: 0.13 (95% confidence interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19) and 0.12 (95% confidence interval 0.04, 0.19)]. We found no evidence of associations between genetically predicted imaging-derived phenotypes and Alzheimer's disease. The inverse association of genetically predicted educational attainment with Alzheimer's disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer's disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer's disease. The protective effect of education on Alzheimer's disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.
Subject(s)
Alzheimer Disease , Cognitive Reserve , Humans , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Alzheimer Disease/genetics , Genome-Wide Association Study , Educational StatusABSTRACT
BACKGROUND: Childhood maltreatment (CM) is a strong risk factor for psychiatric disorders but serves in its current definitions as an umbrella for various fundamentally different childhood experiences. As first step toward a more refined analysis of the impact of CM, our objective is to revisit the relation of abuse and neglect, major subtypes of CM, with symptoms across disorders. METHODS: Three longitudinal studies of major depressive disorder (MDD, N = 1240), bipolar disorder (BD, N = 1339), and schizophrenia (SCZ, N = 577), each including controls (N = 881), were analyzed. Multivariate regression models were used to examine the relation between exposure to abuse, neglect, or their combination to the odds for MDD, BD, SCZ, and symptoms across disorders. Bidirectional Mendelian randomization (MR) was used to probe causality, using genetic instruments of abuse and neglect derived from UK Biobank data (N = 143 473). RESULTS: Abuse was the stronger risk factor for SCZ (OR 3.51, 95% CI 2.17-5.67) and neglect for BD (OR 2.69, 95% CI 2.09-3.46). Combined CM was related to increased risk exceeding additive effects of abuse and neglect for MDD (RERI = 1.4) and BD (RERI = 1.1). Across disorders, abuse was associated with hallucinations (OR 2.16, 95% CI 1.55-3.01) and suicide attempts (OR 2.16, 95% CI 1.55-3.01) whereas neglect was associated with agitation (OR 1.24, 95% CI 1.02-1.51) and reduced need for sleep (OR 1.64, 95% CI 1.08-2.48). MR analyses were consistent with a bidirectional causal effect of abuse with SCZ (IVWforward = 0.13, 95% CI 0.01-0.24). CONCLUSIONS: Childhood abuse and neglect are associated with different risks to psychiatric symptoms and disorders. Unraveling the origin of these differences may advance understanding of disease etiology and ultimately facilitate development of improved personalized treatment strategies.
ABSTRACT
Autistic individuals experience significantly elevated rates of childhood trauma, self-harm and suicidal behaviour and ideation (SSBI). Is this purely the result of negative environmental experiences, or does this interact with genetic predisposition? In this study we investigated if a genetic predisposition for autism is associated with childhood trauma using polygenic scores (PGS) and genetic correlations in the UK Biobank (105,222 < N < 105,638), and tested potential mediators and moderators of the association between autism, childhood trauma and SSBI. Autism PGS were significantly associated with childhood trauma (max R2 = 0.096%, P < 2 × 10-16), self-harm ideation (max R2 = 0.108%, P < 2 × 10-16), and self-harm (max R2 = 0.13%, P < 2 × 10-16). Supporting this, we identified significant genetic correlations between autism and childhood trauma (rg = 0.36 ± 0.05, P = 8.13 × 10-11), self-harm ideation (rg = 0.49 ± 0.05, P = 4.17 × 10-21) and self-harm (rg = 0.48 ± 0.05, P = 4.58 × 10-21), and an over-transmission of PGS for the two SSBI phenotypes from parents to autistic probands. Male sex negatively moderated the effect of autism PGS on childhood trauma (ß = -0.023 ± 0.005, P = 6.74 × 10-5). Further, childhood trauma positively moderated the effect of autism PGS on self-harm score (ß = 8.37 × 10-3 ± 2.76 × 10-3, P = 2.42 × 10-3) and self-harm ideation (ß = 7.47 × 10-3 ± 2.76 × 10-3, P = 6.71 × 10-3). Finally, depressive symptoms, quality and frequency of social interactions, and educational attainment were significant mediators of the effect of autism PGS on SSBI, with the proportion of effect mediated ranging from 0.23 (95% CI: 0.09-0.32) for depression to 0.008 (95% CI: 0.004-0.01) for educational attainment. Our findings identify that a genetic predisposition for autism is associated with adverse life-time outcomes, which represent complex gene-environment interactions, and prioritizes potential mediators and moderators of this shared biology. It is important to identify sources of trauma for autistic individuals in order to reduce their occurrence and impact.
Subject(s)
Autistic Disorder , Self-Injurious Behavior , Autistic Disorder/genetics , Genetic Predisposition to Disease , Humans , Male , Multifactorial Inheritance/genetics , Risk Factors , Self-Injurious Behavior/genetics , Suicidal IdeationABSTRACT
Recent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition. We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macrostructural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed-effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures, and 14 white matter tracts. Other microstructural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate, and prefrontal cortical areas, insula, and hippocampus. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia. Risk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical, and white matter microstructure may be linked to the genetic mechanisms of schizophrenia.
Subject(s)
Schizophrenia , White Matter , Brain/pathology , Genome-Wide Association Study , Humans , Multifactorial Inheritance/genetics , Schizophrenia/pathology , White Matter/pathologyABSTRACT
Previous research indicates a link between autism and transgender and gender-diverse identities, though the association is not yet fully understood. The current study examined autistic traits (Autism Spectrum Quotient [AQ]), empathizing (Empathizing Quotient-Short [EQ-S]), and systemizing (Systemizing Quotient-Short [SQ-S]) in a sample of 89 adults and aimed to test whether gender-diverse individuals exhibit cognitive profiles consistent with predictions derived from the Extreme Male Brain (EMB) theory. As most research has considered only cisgender people, we recruited a more diverse sample by contacting > 200 UK LGBTQ+ organizations and posting on social media. A range of non-cisgender identities (e.g., transgender male, transgender female, non-binary, genderqueer, transmasculine) and non-heterosexual orientations (e.g., bisexual) were represented, and participants were categorized into one of four groups: (1) assigned female at birth but does not identify as female (transgender AFAB) (n = 32), (2) cisgender female (n = 21), (3) assigned male at birth but does not identify as male (transgender AMAB) (n = 18), and (4) cisgender male (n = 18). After controlling for age and autism diagnostic status, transgender AFAB participants had marginally higher AQ scores, and significantly higher SQ-S and systemizing-relative-to-empathizing (D) scores, compared with the cisgender female group. No such differences were detected between the transgender AMAB and cisgender male groups. Our findings are broadly in line with predictions derived from the EMB theory, though as no transgender AFAB participants reported being heterosexual, it was not possible to determine whether these effects relate specifically to gender identity, to sexual orientation, or to both.
Subject(s)
Autistic Disorder , Transgender Persons , Adult , Autistic Disorder/diagnosis , Autistic Disorder/psychology , Brain , Empathy , Female , Gender Identity , Humans , Infant, Newborn , Male , Transgender Persons/psychologyABSTRACT
Assortative mating is a phenomenon in which romantic partners typically resemble each other at a level greater than chance. There is converging evidence that social behaviours are subject to assortative mating, though less is known regarding social cognition. Social functioning requires the ability to identify and understand the mental states of others, i.e., theory of mind. The present study recruited a sample of 102 heterosexual couples via an online survey to test if theory of mind as measured using facial expressions (Reading the Mind in the Eyes Test) or language (Stiller-Dunbar Stories Task) is associated with assortative mating. Results provide evidence of assortative mating for theory of mind via facial expressions, though there was no such effect for theory of mind via language. Assortative mating for theory of mind via facial expressions was not moderated by length of relationship nor by partner similarity in age, educational attainment, or religiosity, all variables relevant to social stratification. This suggests assortative mating for theory of mind via facial expressions is better explained by partners being alike at the start of their relationship (initial assortment) rather than becoming similar through sustained social interaction (convergence), and by people seeking out partners that are like themselves (active assortment) rather than simply pairing with those from similar demographic backgrounds (social homogamy).
ABSTRACT
The Empathizing-Systemizing (E-S) theory of typical sex differences suggests that individuals may be classified based on empathy and systemizing. An extension of the E-S theory, the Extreme Male Brain (EMB) theory suggests that autistic people on average have a shift towards a more masculinized brain along the E-S dimensions. Both theories have been investigated in small sample sizes, limiting their generalizability. Here we leverage two large datasets (discovery n = 671,606, including 36,648 autistic individuals primarily; and validation n = 14,354, including 226 autistic individuals) to investigate 10 predictions of the E-S and the EMB theories. In the discovery dataset, typical females on average showed higher scores on short forms of the Empathy Quotient (EQ) and Sensory Perception Quotient (SPQ), and typical males on average showed higher scores on short forms of the Autism Spectrum Quotient (AQ) and Systemizing Quotient (SQ). Typical sex differences in these measures were attenuated in autistic individuals. Analysis of "brain types" revealed that typical females on average were more likely to be Type E (EQ > SQ) or Extreme Type E and that typical males on average were more likely to be Type S (SQ > EQ) or Extreme Type S. In both datasets, autistic individuals, regardless of their reported sex, on average were "masculinized." Finally, we demonstrate that D-scores (difference between EQ and SQ) account for 19 times more of the variance in autistic traits (43%) than do other demographic variables including sex. Our results provide robust evidence in support of both the E-S and EMB theories.
Subject(s)
Autistic Disorder/psychology , Brain/physiopathology , Adolescent , Adult , Autistic Disorder/physiopathology , Empathy , Female , Humans , Male , Psychological Tests , Sex Factors , Systems Theory , Young AdultABSTRACT
Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected 10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected 10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism.
Subject(s)
Autistic Disorder/genetics , Autistic Disorder/physiopathology , Cerebral Cortex/physiopathology , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/physiopathology , Brain/physiopathology , Brain Mapping/methods , Child , Female , Humans , Magnetic Resonance Imaging , Male , Neuroimaging/methods , Synaptic Transmission/genetics , Transcriptome/geneticsABSTRACT
In the present study, we were interested to investigate how autistic traits (including systemizing and empathy) and academic degree influence individuals' visuospatial abilities. To this end, 352 university students completed the Autism Spectrum Quotient (AQ), the Empathy Quotient, the Systemizing Quotient (SQ) and visuospatial tests measuring figure disembedding and mental rotation of two-dimensional figures. Engineering-design students (architecture and engineering) were the most accurate in disembedding and mentally rotating figures, followed by students of physical sciences (computer science, chemistry, physics, etc.) and fact-based humanities (languages, classics, law); biological (psychology and neuroscience, etc.) and systems-based social scientists (economics and commerce) were the least accurate. Engineering-design students also showed higher SQ scores with respect to the other four academic degree subjects, with students of biological sciences showing lower SQ scores. Importantly, results from a path analysis revealed that SQ (but not AQ) exerted an indirect effect on figure disembedding and mental rotations through the influence of the academic degree. Thus, the present findings reveal shady differences in systemizing degree and visuospatial performance within systemizing-based degree subjects. Implications for education are discussed.
Subject(s)
Autistic Disorder/psychology , Educational Status , Spatial Navigation , Visual Perception , Empathy , Engineering/education , Female , Humans , Imagination , Male , Mathematics/education , Natural Science Disciplines , Psychiatric Status Rating Scales , Psychomotor Performance , Rotation , Science/education , Sex Characteristics , Students , Young AdultABSTRACT
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that mainly affect children and are grouped together by similar clinical features and the accumulation of autofluorescent storage material. More than a dozen genes containing nearly 400 mutations underlying human NCLs have been identified. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity and progression. There are still disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
Subject(s)
Genetic Predisposition to Disease , Membrane Proteins/genetics , Mutation/genetics , Neuronal Ceroid-Lipofuscinoses/genetics , Neuronal Ceroid-Lipofuscinoses/pathology , Humans , PhenotypeABSTRACT
Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated the sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals, then compared effect sizes between individuals with and without cognitive impairment or motor delay. Although these variants mediated differential likelihood of autism with versus without motor or cognitive impairment, their effect sizes on the liability scale did not differ significantly by sex exome-wide or in genes sex-differentially expressed in the cortex. Although de novo mutations were enriched in genes with male-biased expression in the fetal cortex, the liability they conferred did not differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. In summary, autosomal rare coding variants confer similar liability for autism in females and males.
ABSTRACT
Gambling Disorder (GD) is an impactful behavioural addiction for which there appear to be underpinning genetic contributors. Twin studies show significant GD heritability results and intergenerational transmission show high rates of transmission. Recent developments in polygenic and multifactorial risk prediction modelling provide promising opportunities to enable early identification and intervention for at risk individuals. People with GD often have significant delays in diagnosis and subsequent help-seeking that can compromise their recovery. In this paper we advocate for more research into the utility of polygenic and multifactorial risk modelling in GD research and treatment programs and rigorous evaluation of its costs and benefits.
Subject(s)
Behavior, Addictive , Gambling , Humans , Gambling/genetics , Risk AssessmentABSTRACT
Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been shown to have larger brain volumes than females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development, which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell-derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from individuals with autism and individuals with X chromosome-linked Rett syndrome and fragile X syndrome have revealed prenatal differences in cell proliferation, a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids have also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review, we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. Then, we examine the role of X chromosome inactivation as a factor that drives sex differences. Finally, we discuss the combined challenges of modeling X chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.
Sex differences are a contributing factor in neuropsychiatric conditions such as autism, which is more prevalent in males. Sex differences occur through interactions between sex steroid hormones such as estrogen and testosterone and sex chromosomes (chrX and chrY). Human stem cellderived brain organoids are laboratory models that mimic brain development. For example, in individuals with neurodevelopmental conditions, brain organoids have revealed an imbalance of neuron populations compared with neurotypical individuals. In this review, we discuss sex steroid and sex chromosome influences on brain development and challenges of this model that need to be taken into account when studying sex differences.
ABSTRACT
Importance: Suicide is the third-leading cause of death among US adolescents. Environmental and lifestyle factors influence suicidal behavior and can inform risk classification, yet quantifying and incorporating them in risk assessment presents a significant challenge for reproducibility and clinical translation. Objective: To quantify the aggregate contribution of environmental and lifestyle factors to youth suicide attempt risk classification. Design, Setting, and Participants: This was a cohort study in 3 youth samples: 2 national longitudinal cohorts from the US and the UK and 1 clinical cohort from a tertiary pediatric US hospital. An exposome-wide association study (ExWAS) approach was used to identify risk and protective factors and compute aggregate exposomic scores. Logistic regression models were applied to test associations and model fit of exposomic scores with suicide attempts in independent data. Youth from the Adolescent Brain Cognitive Development (ABCD) study, the UK Millennium Cohort Study (MCS), and the Children's Hospital of Philadelphia emergency department (CHOP-ED) were included in the study. Exposures: A single-weighted exposomic score that sums significant risk and protective environmental/lifestyle factors. Main Outcome and Measure: Self-reported suicide attempt. Results: A total of 40â¯364 youth were included in this analysis: 11â¯564 from the ABCD study (3 waves of assessment; mean [SD] age, 12.0 [0.7] years; 6034 male [52.2%]; 344 attempted suicide [3.0%]; 1154 environmental/lifestyle factors were included in the ABCD study), 9000 from the MCS cohort (mean [SD] age, 17.2 [0.3] years; 4593 female [51.0%]; 661 attempted suicide [7.3%]; 2864 environmental/lifestyle factors were included in the MCS cohort), and 19â¯800 from the CHOP-ED cohort (mean [SD] age, 15.3 [1.5] years; 12â¯937 female [65.3%]; 2051 attempted suicide [10.4%]; 36 environmental/lifestyle factors were included in the CHOP-ED cohort). In the ABCD discovery subsample, ExWAS identified 99 risk and protective exposures significantly associated with suicide attempt. A single weighted exposomic score that sums significant risk and protective exposures was associated with suicide attempt in an independent ABCD testing subsample (odds ratio [OR], 2.2; 95% CI, 2.0-2.6; P < .001) and explained 17.6% of the variance (based on regression pseudo-R2) in suicide attempt over and above that explained by age, sex, race, and ethnicity (2.8%) and by family history of suicide (6.3%). Findings were consistent in the MCS and CHOP-ED cohorts (explaining 22.6% and 19.3% of the variance in suicide attempt, respectively) despite clinical, demographic, and exposure differences. In all cohorts, compared with youth at the median quintile of the exposomic score, youth at the top fifth quintile were substantially more likely to have made a suicide attempt (OR, 4.3; 95% CI, 2.6-7.2 in the ABCD study; OR, 3.8; 95% CI, 2.7-5.3 in the MCS cohort; OR, 5.8; 95% CI, 4.7-7.1 in the CHOP-ED cohort). Conclusions and Relevance: Results suggest that exposomic scores of suicide attempt provided a generalizable method for risk classification that can be applied in diverse samples from clinical or population settings.
ABSTRACT
Recent work has leveraged massive datasets and advanced harmonization methods to construct normative models of neuroanatomical features and benchmark individuals' morphology. However, current harmonization tools do not preserve the effects of biological covariates including sex and age on features' variances; this failure may induce error in normative scores, particularly when such factors are distributed unequally across sites. Here, we introduce a new extension of the popular ComBat harmonization method, ComBatLS, that preserves biological variance in features' locations and scales. We use UK Biobank data to show that ComBatLS robustly replicates individuals' normative scores better than other ComBat methods when subjects are assigned to sex-imbalanced synthetic "sites". Additionally, we demonstrate that ComBatLS significantly reduces sex biases in normative scores compared to traditional methods. Finally, we show that ComBatLS successfully harmonizes consortium data collected across over 50 studies. R implementation of ComBatLS is available at https://github.com/andy1764/ComBatFamily.
ABSTRACT
Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4,928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.