Microstructural neural correlates of maximal grip strength in autistic children: the role of the cortico-cerebellar network and attention-deficit/hyperactivity disorder features.

Introduction: Maximal grip strength, a measure of how much force a person's hand can generate when squeezing an object, may be an effective method for understanding potential neurobiological differences during motor tasks. Grip strength in autistic individuals may be of particular interest due to its unique developmental trajectory. While autism-specific differences in grip-brain relationships have been found in adult populations, it is possible that such differences in grip-brain relationships may be present at earlier ages when grip strength is behaviorally similar in autistic and non-autistic groups. Further, such neural differences may lead to the later emergence of diagnostic-group grip differences in adolescence. The present study sought to examine this possibility, while also examining if grip strength could elucidate the neuro-motor sources of phenotypic heterogeneity commonly observed within autism. Methods: Using high resolution, multi-shell diffusion, and quantitative R1 relaxometry imaging, this study examined how variations in key sensorimotor-related white matter pathways of the proprioception input, lateral grasping, cortico-cerebellar, and corticospinal networks were associated with individual variations in grip strength in 68 autistic children and 70 non-autistic (neurotypical) children (6-11 years-old). Results: In both groups, results indicated that stronger grip strength was associated with higher proprioceptive input, lateral grasping, and corticospinal (but not cortico-cerebellar modification) fractional anisotropy and R1, indirect measures concordant with stronger microstructural coherence and increased myelination. Diagnostic group differences in these grip-brain relationships were not observed, but the autistic group exhibited more variability particularly in the cortico-cerebellar modification indices. An examination into the variability within the autistic group revealed that attention-deficit/hyperactivity disorder (ADHD) features moderated the relationships between grip strength and both fractional anisotropy and R1 relaxometry in the premotor-primary motor tract of the lateral grasping network and the cortico-cerebellar network tracts. Specifically, in autistic children with elevated ADHD features (60% of the autistic group) stronger grip strength was related to higher fractional anisotropy and R1 of the cerebellar modification network (stronger microstructural coherence and more myelin), whereas the opposite relationship was observed in autistic children with reduced ADHD features. Discussion: Together, this work suggests that while the foundational elements of grip strength are similar across school-aged autistic and non-autistic children, neural mechanisms of grip strength within autistic children may additionally depend on the presence of ADHD features. Specifically, stronger, more coherent connections of the cerebellar modification network, which is thought to play a role in refining and optimizing motor commands, may lead to stronger grip in children with more ADHD features, weaker grip in children with fewer ADHD features, and no difference in grip in non-autistic children. While future research is needed to understand if these findings extend to other motor tasks beyond grip strength, these results have implications for understanding the biological basis of neuromotor control in autistic children and emphasize the importance of assessing co-occurring conditions when evaluating brain-behavior relationships in autism.

Sensorimotor Features and Daily Living Skills in Autistic Children With and Without ADHD.

Attention-deficit/hyperactivity disorder (ADHD) commonly co-occurs in autistic children. However, additional research is needed to explore the differences in motor skills and sensory features in autistic children with and without ADHD, as well as the impacts of these factors on daily living skills (DLS). This observational study sought to fill this gap with 67 autistic children (6.14-10.84 years-old), 43 of whom had ADHD. Autistic children with ADHD demonstrated higher sensory features and lower motor skills than autistic children without ADHD. In examining autism and ADHD features dimensionally, we found that overall sensory features, seeking, and hyporesponsiveness were driven by both autism and ADHD features, whereas motor skills, enhanced perception, and hyperresponsiveness were driven by only autism features. Additionally, in using these dimensional variables of autism and ADHD features, we found that differences in motor skills, sensory and autism features, but not ADHD features, impact DLS of autistic children, with autism features and motor skills being the strongest individual predictors of DLS. Together, these results demonstrate the uniqueness of motor skills and sensory features in autistic children with and without ADHD, as well as how autism features, sensory features, and motor skills contribute to DLS, emphasizing the importance of a comprehensive understanding of each individual and complexities of human development when supporting autistic children.

Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort.

BACKGROUND: ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. METHODS: Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. RESULTS: A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. CONCLUSIONS: The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.

Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies.

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.

A prospective longitudinal study of multidomain resilience among youths with and without maltreatment histories.

The majority of children with maltreatment histories do not go on to develop depression in their adolescent and adult years. These individuals are often identified as being "resilient", but this characterization may conceal difficulties that individuals with maltreatment histories might face in their interpersonal relationships, substance use, physical health, and/or socioeconomic outcomes in their later lives. This study examined how adolescents with maltreatment histories who exhibit low levels of depression function in other domains during their adult years. Longitudinal trajectories of depression (across ages 13-32) in individuals with (n = 3,809) and without (n = 8,249) maltreatment histories were modeled in the National Longitudinal Study of Adolescent to Adult Health. The same "Low," "increasing," and "declining" depression trajectories in both individuals with and without maltreatment histories were identified. Youths with maltreatment histories in the "low" depression trajectory reported lower romantic relationship satisfaction, more exposure to intimate partner and sexual violence, more alcohol abuse/dependency, and poorer general physical health compared to individuals without maltreatment histories in the same "low" depression trajectory in adulthood. Findings add further caution against labeling individuals as "resilient" based on a just single domain of functioning (low depression), as childhood maltreatment has harmful effects on a broad spectrum of functional domains.

Research Domain Criteria (RDoC) mechanisms of transdiagnostic polygenic risk for trajectories of depression: From early adolescence to adulthood.

There is substantial heterogeneity in the development of depression from adolescence into adulthood. Yet, little is known about the risk factors underlying its various patterns of development. For instance, despite the discovery of genetic variants for depression, these discoveries have not accounted for the high degree of genetic covariation between multiple disorders, nor have they been applied to disambiguate its heterogeneous developmental presentations. This study examined the association between a transdiagnostic polygenic score for psychopathology (p-factor PGS) and depression trajectories, spanning early adolescence into adulthood, in the National Longitudinal Study of Adolescent to Adult Health (N = 7,088). We examined whether subconstructs of the Research Domain Criteria's (RDoC) negative valence (i.e., negative emotionality), positive valence (i.e., novelty seeking), and cognitive systems (i.e., picture vocabulary) could explain how the p-factor PGS eventuates into the various pathways of depression. Four trajectories were identified: low depression (78.9%), low increasing (7.3%), high declining (8.2%), and early adult peaked (5.7%). The p-factor PGS was significantly higher in all depressive trajectories relative to the low-depression trajectory but was predictive of only the trajectory that showed increasing depression over time: low increasing. A specific indirect path emerged by which the association of p-factor PGS on early adult peaked and high-declining depression operated through the effects of negative emotionality but not picture vocabulary or novelty seeking. Findings reinforce the crucial role of development in genetically informed RDoC models of depression, because there appear to be distinct correlates and risk factors that underlie the various developmental pathways of depression. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Explaining the Prospective Association of Positive and Negative Parenting Behaviors and Child ADHD Symptoms: Pathways Through Child Executive Function and Reward Responsivity.

Objective: Parenting behavior is a well-established correlate of offspring ADHD. However, little is known about how parenting exerts its effects on offspring ADHD symptomatology. We examined whether prospective associations between positive and negative parenting behaviors and child ADHD symptoms are mediated by deficits in child executive function (EF) and reward responsivity (RR). Method: One hundred and thirty-five children with and without ADHD were assessed across two Waves, when children were mean ages 6 and 8 respectively. Children completed tasks on EF, and parents completed questionnaires about their parenting behaviors and their children's RR and ADHD symptoms. Results: Negative parenting behavior at Wave 1 was indirectly associated with offspring ADHD symptoms at Wave 2 via offspring EF. Conclusion: Individual differences in EF, but not RR, during early childhood may constitute a potential pathway by which negative parenting behaviors exerts its effects on subsequent offspring ADHD symptomatology. Treatment implications are discussed.

The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research.

The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.

Childhood exposure to interpersonal violence is associated with greater transdiagnostic integration of psychiatric symptoms.

BACKGROUND: Childhood exposure to interpersonal violence (IPV) may be linked to distinct manifestations of mental illness, yet the nature of this change remains poorly understood. Network analysis can provide unique insights by contrasting the interrelatedness of symptoms underlying psychopathology across exposed and non-exposed youth, with potential clinical implications for a treatment-resistant population. We anticipated marked differences in symptom associations among IPV-exposed youth, particularly in terms of 'hub' symptoms holding outsized influence over the network, as well as formation and influence of communities of highly interconnected symptoms. METHODS: Participants from a population-representative sample of youth (n = 4433; ages 11-18 years) completed a comprehensive structured clinical interview assessing mental health symptoms, diagnostic status, and history of violence exposure. Network analytic methods were used to model the pattern of associations between symptoms, quantify differences across diagnosed youth with (IPV+) and without (IPV-) IPV exposure, and identify transdiagnostic 'bridge' symptoms linking multiple disorders. RESULTS: Symptoms organized into six 'disorder' communities (e.g. Intrusive Thoughts/Sensations, Depression, Anxiety), that exhibited considerably greater interconnectivity in IPV+ youth. Five symptoms emerged in IPV+ youth as highly trafficked 'bridges' between symptom communities (11 in IPV- youth). CONCLUSION: IPV exposure may alter mutually reinforcing symptom co-occurrence in youth, thus contributing to greater psychiatric comorbidity and treatment resistance. The presence of a condensed and unique set of bridge symptoms suggests trauma-enriched nodes which could be therapeutically targeted to improve outcomes in violence-exposed youth.

A Gene-Environment Interaction Study of Polygenic Scores and Maltreatment on Childhood ADHD.

This study explored whether maltreatment moderates the association of polygenic risk for ADHD. Because individuals with low polygenic scores (PGS) for ADHD were previously shown to have better than expected functional outcomes (i.e., cognitive, mental health, social-emotional) than individuals with middle or high ADHD PGS, we hypothesized low ADHD PGS may confer a protective effect from maltreatment in the development of ADHD. Data were from participants with phenotypic and genotypic data in the National Longitudinal Study of Adolescent to Adult Health (Add Health; n = 4,722). ADHD PGS were generated from the most recent genome-wide association study on ADHD and categorized into three groups (i.e., low, medium, high) using empirically determined cut-points. A maltreatment factor score was derived from five forms of self-reported maltreatment experiences prior to age 18. ADHD PGS and maltreatment were positively associated with ADHD symptoms, as expected. However, no interaction between ADHD PGS and maltreatment on ADHD symptoms was detected. Despite the increase in predictive power afforded by PGS, the lack of an interaction between ADHD PGS and maltreatment on ADHD symptoms converges with an emerging body of PGS studies that have also failed to detect PGS-environment interplay in mental disorders. We discuss possible reasons for this pattern of results and offer alternative methods for future research in understanding gene-environment interactions.

SUPERGNOVA: local genetic correlation analysis reveals heterogeneous etiologic sharing of complex traits.

Local genetic correlation quantifies the genetic similarity of complex traits in specific genomic regions. However, accurate estimation of local genetic correlation remains challenging, due to linkage disequilibrium in local genomic regions and sample overlap across studies. We introduce SUPERGNOVA, a statistical framework to estimate local genetic correlations using summary statistics from genome-wide association studies. We demonstrate that SUPERGNOVA outperforms existing methods through simulations and analyses of 30 complex traits. In particular, we show that the positive yet paradoxical genetic correlation between autism spectrum disorder and cognitive performance could be explained by two etiologically distinct genetic signatures with bidirectional local genetic correlations.

Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies.

Marginal effect estimates in genome-wide association studies (GWAS) are mixtures of direct and indirect genetic effects. Existing methods to dissect these effects require family-based, individual-level genetic, and phenotypic data with large samples, which is difficult to obtain in practice. Here, we propose a statistical framework to estimate direct and indirect genetic effects using summary statistics from GWAS conducted on own and offspring phenotypes. Applied to birth weight, our method showed nearly identical results with those obtained using individual-level data. We also decomposed direct and indirect genetic effects of educational attainment (EA), which showed distinct patterns of genetic correlations with 45 complex traits. The known genetic correlations between EA and higher height, lower body mass index, less-active smoking behavior, and better health outcomes were mostly explained by the indirect genetic component of EA. In contrast, the consistently identified genetic correlation of autism spectrum disorder (ASD) with higher EA resides in the direct genetic component. A polygenic transmission disequilibrium test showed a significant overtransmission of the direct component of EA from healthy parents to ASD probands. Taken together, we demonstrate that traditional GWAS approaches, in conjunction with offspring phenotypic data collection in existing cohorts, could greatly benefit studies on genetic nurture and shed important light on the interpretation of genetic associations for human complex traits.

Detecting local genetic correlations with scan statistics.

Genetic correlation analysis has quickly gained popularity in the past few years and provided insights into the genetic etiology of numerous complex diseases. However, existing approaches oversimplify the shared genetic architecture between different phenotypes and cannot effectively identify precise genetic regions contributing to the genetic correlation. In this work, we introduce LOGODetect, a powerful and efficient statistical method to identify small genome segments harboring local genetic correlation signals. LOGODetect automatically identifies genetic regions showing consistent associations with multiple phenotypes through a scan statistic approach. It uses summary association statistics from genome-wide association studies (GWAS) as input and is robust to sample overlap between studies. Applied to seven phenotypically distinct but genetically correlated neuropsychiatric traits, we identify 227 non-overlapping genome regions associated with multiple traits, including multiple hub regions showing concordant effects on five or more traits. Our method addresses critical limitations in existing analytic strategies and may have wide applications in post-GWAS analysis.

Polygenic Scores for ADHD: A Meta-Analysis.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that is known to have a polygenic (i.e., many genes of individually small effects) architecture. Polygenic scores (PGS), which characterize this polygenicity as a single score for a given individual, are considered the state-of-the-art in psychiatric genetics research. Despite the proliferation of ADHD studies adopting this approach and its clinical implications, remarkably little is known about the predictive utility of PGS in ADHD research to date, given that there have not yet been any systematic or meta-analytic reviews of this rapidly developing literature. We meta-analyzed 12 unique effect sizes from ADHD PGS studies, yielding an N = 40,088. These studies, which included a mixture of large population-based cohorts and case-control samples of predominantly European ancestry, yielded a pooled ADHD PGS effect size of rrandom = 0.201 (95% CI = [0.144, 0.288]) and an rfixed = 0.190 (95% CI = [0.180, 0.199]) in predicting ADHD. In other words, ADHD PGS reliably account for between 3.6% (in the fixed effects model) to 4.0% (in the random effects model) of the variance in broadly defined phenotypic ADHD. Findings provide important insights into the genetics of psychiatric outcomes and raise several key questions about the impact of PGS on psychiatric research moving forward. Our review concludes by providing recommendations for future research directions in the use of PGS, including new methods to account for comorbidities, integrating bioinformatics to elucidate biological pathways, and leveraging PGS to test mechanistic models of ADHD.

The positive end of the polygenic score distribution for ADHD: a low risk or a protective factor?

BACKGROUND: Polygenic scores (PGS) are widely used to characterize genetic liability for heritable mental disorders, including attention-deficit/hyperactivity disorder (ADHD). However, little is known about the effects of a low burden of genetic liability for ADHD, including whether this functions as a low risk or protective factor for ADHD and related functional outcomes in later life. The current study examines the association of low ADHD PGS and functional outcomes in adulthood. METHODS: Participants were from Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health) (N = 7088; mean age = 29, s.d. = 1.74). ADHD PGS was computed from an existing genome-wide association study, and adult functional outcomes, including cognition, educational attainment, mental health, and physical health were assessed during in-home interviews. RESULTS: Individuals at the lowest end of the ADHD PGS distribution (i.e. lowest 20th percentile) had the lowest probabilities of ADHD, exhibiting a 17-19% reduction in risk for ADHD relative to the observed 8.3% prevalence rate of ADHD in Add Health. Furthermore, individuals with low ADHD PGS had higher cognitive performance, greater levels of educational attainment, and lower BMI relative to individuals representing the rest of the ADHD PGS distribution, including those who were in the medium and high-PGS groups. CONCLUSIONS: Findings indicate that psychiatric PGS likely capture far more than just the risk and the absence of risk for a psychiatric outcome; where one lies along the PGS distribution may predict diverging functional consequences, for better and for worse.

Factorial invariance in hierarchical factor models of mental disorders in African American and European American youths.

BACKGROUND: There is converging evidence that mental disorders are more optimally conceptualized in a hierarchical framework (i.e., the Hierarchical Taxonomy of Psychopathology, HiTOP) that transcends the categorical boundaries of the Diagnostic and Statistical Manual of Mental Disorders (DSM). However, the majority of this evidence comes from studies that draw upon predominantly European American or Caucasian populations. Whether a hierarchical conceptualization of mental disorders generalizes across racial-ethnic groups, including for African American (AA) populations, is unclear. METHODS: We tested multidimensional and bifactor models of 15 DSM diagnoses and psychiatric traits in two groups, including AA (n = 3,088) and European American (EA; n = 5,147) youths aged 8-21 from the Philadelphia Neurodevelopmental Cohort (PNC). We also conducted multigroup confirmatory factor analyses to test for factorial invariance between the best fitting AA and EA multidimensional and bifactor models. RESULTS: In the multidimensional model tests, a three-factor model, specifying internalizing, externalizing, and thought dimensions, emerged as the best fitting model for AAs and EAs. In the bifactor model tests, a three-factor model (i.e., internalizing, externalizing, and thought dimensions) that also specified a general factor emerged as the optimal for both AAs and EAs. The general factor accounted for a significant proportion of the covariation between the secondary factors and the individual disorders and traits. Furthermore, both models were factorially invariant, indicating no significant difference in the factor structure of mental disorders between AAs and EAs in PNC. CONCLUSIONS: Results suggest that the hierarchical factor structure of mental disorders may be racial-ethnically robust. This finding has implications for etiological and epidemiological studies focused on racial-ethnic subgroup comparisons, particularly with respect to identifying similarities and differences in prevalence rates or sociodemographic risk factors for mental disorders.

The impact of parenting a child with serious mental illness: Accounting for the parent's genetic vulnerability to mental illness.

Parents of adults with serious mental illness (SMI) often are primary caregivers for their affected relative. Prior work has suggested that the toll of caregiving is associated with poorer well-being in family caregivers, particularly parents of affected adults. However, due to methodological limitations, it has not been possible to assess these family caregivers' own genetic vulnerability to mental and physical health problems, and thus the impact of caregivers' genetic risk on well-being may not have been accounted for. With the addition of genetic data to large survey samples, family caregivers' genetic vulnerability to mental and physical health problems can now be estimated. Parents from the Wisconsin Longitudinal Study who have an adult child with an SMI (n = 265) and a comparison group of parents with a child without disabilities (n = 5,036) reported their psychological well-being and mental and physical health across 4 measures. Genetic vulnerability was assessed using polygenic risk scores of neuroticism, bipolar disorder, schizophrenia, and depression. Results indicate that the effect of having a child with an SMI still had significant effects for all 4 parental health outcomes even after controlling for these measures of genetic vulnerability. This study's results affirm the negative health impact of parenting a child with SMI, above and beyond genetic vulnerability. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Assessing phenotypic and polygenic models of ADHD to identify mechanisms of risk for longitudinal trajectories of externalizing behaviors.

BACKGROUND: Children with ADHD frequently engage in higher rates of externalizing behaviors in adulthood relative to children without. However, externalizing behaviors vary across development. Little is known about how this risk unfolds across development. Phenotypic and polygenic models of childhood ADHD were used to predict individual differences in adult externalizing trajectories. Supportive parenting, school connectedness, and peer closeness were then examined as causal mechanisms. METHODS: Data were from the National Longitudinal Study of Adolescent to Adult Health (N = 7,674). Externalizing behavior was measured using data from age 18 to 32 and modeled using latent class growth analysis. Child ADHD was measured using retrospective self-report (phenotypic model) and genome-wide polygenic risk scores (polygenic model). Multiple mediation models examined the direct and indirect effects of the phenotypic and polygenic models (separately) on externalizing trajectories through the effects of adolescent supportive parenting, school connectedness, and peer closeness. RESULTS: Phenotypic and polygenic models of ADHD were associated with being in the High Decreasing (3.2% of sample) and Moderate (16.1%) adult externalizing trajectories, but not the severe Low Increasing trajectory (2.6%), relative to the Normal trajectory (78.2%). Associations between both models of ADHD on the High Decreasing and Moderate trajectories were partially mediated through the effects of school connectedness, but not supportive parenting or peer closeness. CONCLUSIONS: Findings shed light on how childhood ADHD affects downstream psychosocial processes that then predict specific externalizing outcomes in adulthood. They also reinforce the importance of fostering a strong school environment for adolescents with (and without) ADHD, as this context plays a critical role in shaping the development of externalizing behaviors in adulthood.

Genome-wide association study reveals sex-specific genetic architecture of facial attractiveness.

Facial attractiveness is a complex human trait of great interest in both academia and industry. Literature on sociological and phenotypic factors associated with facial attractiveness is rich, but its genetic basis is poorly understood. In this paper, we conducted a genome-wide association study to discover genetic variants associated with facial attractiveness using 4,383 samples in the Wisconsin Longitudinal Study. We identified two genome-wide significant loci, highlighted a handful of candidate genes, and demonstrated enrichment for heritability in human tissues involved in reproduction and hormone synthesis. Additionally, facial attractiveness showed strong and negative genetic correlations with BMI in females and with blood lipids in males. Our analysis also suggested sex-specific selection pressure on variants associated with lower male attractiveness. These results revealed sex-specific genetic architecture of facial attractiveness and provided fundamental new insights into its genetic basis.