Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders.

Methods of estimating polygenic scores (PGSs) from genome-wide association studies are increasingly utilized. However, independent method evaluation is lacking, and method comparisons are often limited. Here, we evaluate polygenic scores derived via seven methods in five biobank studies (totaling about 1.2 million participants) across 16 diseases and quantitative traits, building on a reference-standardized framework. We conducted meta-analyses to quantify the effects of method choice, hyperparameter tuning, method ensembling, and the target biobank on PGS performance. We found that no single method consistently outperformed all others. PGS effect sizes were more variable between biobanks than between methods within biobanks when methods were well tuned. Differences between methods were largest for the two investigated autoimmune diseases, seropositive rheumatoid arthritis and type 1 diabetes. For most methods, cross-validation was more reliable for tuning hyperparameters than automatic tuning (without the use of target data). For a given target phenotype, elastic net models combining PGS across methods (ensemble PGS) tuned in the UK Biobank provided consistent, high, and cross-biobank transferable performance, increasing PGS effect sizes (β coefficients) by a median of 5.0% relative to LDpred2 and MegaPRS (the two best-performing single methods when tuned with cross-validation). Our interactively browsable online-results and open-source workflow prspipe provide a rich resource and reference for the analysis of polygenic scoring methods across biobanks.

BACKGROUND: Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population.
METHODS: To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families).
RESULTS: We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D2 on the order of 1 × 10-5).
CONCLUSIONS: We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification.
CONCLUSIONS: This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis.

Digital media (DM) takes an increasingly large part of children\'s time, yet the long-term effect on brain development remains unclear. We investigated how individual effects of DM use (i.e., using social media, playing video games, or watching television/videos) on the development of the cortex (i.e., global cortical surface area), striatum, and cerebellum in children over 4 years, accounting for both socioeconomic status and genetic predisposition. We used a prospective, multicentre, longitudinal cohort of children from the Adolescent Brain and Cognitive Development Study, aged 9.9 years when entering the study, and who were followed for 4 years. Annually, children reported their DM usage through the Youth Screen Time Survey and underwent brain magnetic resonance imaging scans every 2 years. Quadratic-mixed effect modelling was used to investigate the relationship between individual DM usage and brain development. We found that individual DM usage did not alter the development of cortex or striatum volumes. However, high social media usage was associated with a statistically significant change in the developmental trajectory of cerebellum volumes, and the accumulated effect of high-vs-low social media users on cerebellum volumes over 4 years was only β = - 0.03, which was considered insignificant. Nevertheless, the developmental trend for heavy social media users was accelerated at later time points. This calls for further studies and longer follow-ups on the impact of social media on brain development.

UNASSIGNED: Vitamin D deficiency has been associated with psychiatric disorders and behavioral phenotypes such as Attention-Deficit/Hyperactivity Disorder (ADHD). Considering that vitamin D levels are polygenic, we aim to evaluate the overall effects of its genetic architecture on symptoms of inattention, hyperactivity, and impulsivity and on the serum levels of vitamin D in two independent samples of adults, as well as the specific effects of five relevant polymorphisms in vitamin D-related genes.
UNASSIGNED: We evaluated 870 subjects from an ADHD sample (407 cases and 463 controls) and 319 subjects from an academic community (nutrigenetic sample). Vitamin D serum levels were obtained through Elisa test and genetic data by TaqMan™ allelic discrimination and Infinium PsychArray-24 BeadChip genotyping. Polygenic Scores (PGS) were calculated on PRSice2 based on the latest GWAS for Vitamin D and statistical analyses were conducted at Plink and SPSS software.
UNASSIGNED: Vitamin D PGSs were associated with inattention in the ADHD sample and with hyperactivity when inattention symptoms were included as covariates. In the nutrigenetic sample, CYP2R1 rs10741657 and DHCR7 rs12785878 were nominally associated with impulsivity and hyperactivity, respectively, and both with vitamin D levels. In the clinical sample, RXRG rs2134095 was associated with impulsivity.
UNASSIGNED: Our findings suggest a shared genetic architecture between vitamin D levels and ADHD symptoms, as evidenced by the associations observed with PGS and specific genes related to vitamin D levels. Interestingly, differential effects for vitamin D PGS were found in inattention and hyperactivity, which should be considered in further studies involving ADHD.

Genome-wide association studies (GWASs) have identified specific genetic variants associated with complex human traits and behaviors, such as educational attainment, mental disorders, and personality. However, small effect sizes for individual variants, uncertainty regarding the biological function of discovered genotypes, and potential \"outside-the-skin\" environmental mechanisms leave a translational gulf between GWAS results and scientific understanding that will improve human health and well-being. We propose a set of social, behavioral, and brain-science research activities that map discovered genotypes to neural, developmental, and social mechanisms and call this research program phenotypic annotation. Phenotypic annotation involves (a) elaborating the nomological network surrounding discovered genotypes, (b) shifting focus from individual genes to whole genomes, and (c) testing how discovered genotypes affect life-span development. Phenotypic-annotation research is already advancing the understanding of GWAS discoveries for educational attainment and schizophrenia. We review examples and discuss methodological considerations for psychologists taking up the phenotypic-annotation approach.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk.
METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones.
RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20).
CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Polygenic scores (PGSs) summarize the combined effect of common risk variants and are associated with breast cancer risk in patients without identifiable monogenic risk factors. One of the most well-validated PGSs in breast cancer to date is PGS313, which was developed from a Northern European biobank but has shown attenuated performance in non-European ancestries. We further investigate the generalizability of the PGS313 for American women of European (EA), African (AFR), Asian (EAA), and Latinx (HL) ancestry within one institution with a singular electronic health record (EHR) system, genotyping platform, and quality control process. We found that the PGS313 achieved overlapping areas under the receiver operator characteristic (ROC) curve (AUCs) in females of HL (AUC = 0.68, 95% confidence interval [CI] = 0.65-0.71) and EA ancestry (AUC = 0.70, 95% CI = 0.69-0.71) but lower AUCs for the AFR and EAA populations (AFR: AUC = 0.61, 95% CI = 0.56-0.65; EAA: AUC = 0.64, 95% CI = 0.60-0.680). While PGS313 is associated with hormone-receptor-positive (HR+) disease in EA Americans (odds ratio [OR] = 1.42, 95% CI = 1.16-1.64), this association is lost in African, Latinx, and Asian Americans. In summary, we found that PGS313 was significantly associated with breast cancer but with attenuated accuracy in women of AFR and EAA descent within a singular health system in Los Angeles. Our work further highlights the need for additional validation in diverse cohorts prior to the clinical implementation of PGSs.

UNASSIGNED: Difficulty with self-control, or the ability to alter impulses and behavior in a goal-directed way, predicts interpersonal conflict, lower socioeconomic attainments, and more adverse health outcomes. Etiological understanding, and intervention for low self-control is, therefore, a public health goal. A prominent developmental theory proposes that individuals with high genetic propensity for low self-control that are also exposed to stressful environments may be most at-risk of low levels of self-control. Here we examine if polygenic measures associated with behaviors marked by low self-control interact with stressful life events in predicting self-control.
UNASSIGNED: Leveraging molecular data from a large population-based Dutch sample (N = 7,090, Mage = 41.2) to test for effects of genetics (i.e., polygenic scores for ADHD and aggression), stressful life events (e.g., traffic accident, violent assault, financial problems), and a gene-by-stress interaction on self-control (measured with the ASEBA Self-Control Scale).
UNASSIGNED: Both genetics (β =.03 -.04, p <.001) and stressful life events (β = .11 -.14, p <.001) were associated with individual differences in self-control. We find no evidence of a gene-by-stressful life events interaction on individual differences in adults\' self-control.
UNASSIGNED: Our findings are consistent with the notion that genetic influences and stressful life events exert largely independent effects on adult self-control. However, the small effect sizes of polygenic scores increases the likelihood of null results. Genetically-informed longitudinal research in large samples can further inform the etiology of individual differences in self-control from early childhood into later adulthood and its downstream implications for public health.

There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly understood. Microglia play a role in environmental surveillance and may influence individual susceptibility to environmental factors. As an index of neurodevelopment, we estimated individual slopes of mean white matter fractional anisotropy (WM-FA) across three time-points (age 4.5, 6.0, and 7.5 years) for 351 participants. Individual variation in microglia reactivity was derived from an expression-based polygenic score(ePGS) comprised of Single Nucleotide Polymorphisms (SNPs) functionally related to the expression of microglia-enriched genes.A higher ePGS denotes an increased genetic capacity for the expression of microglia-related genes, and thus may confer a greater capacity to respond to the early environment and to influence brain development. We hypothesized that this ePGS would associate with the WM-FA index of neurodevelopment and moderate the influence of early environmental factors.Our findings show sex dependency, where a significant association between WM-FA and microglia ePGS was only obtained for females.We then examined associations with perinatal factors known to decrease (optimal birth outcomes and familial conditions) or increase (systemic inflammation) the risk for later mental health problems.In females, individuals with high microglia ePGS showed a negative association between systemic inflammation and WM-FA and a positive association between more advantageous environmental conditions and WM-FA. The microglia ePGS in females thus accounted for variations in the influence of the quality of the early environment on WM-FA.Finally, WM-FA slopes mediated the association of microglia ePGS with interpersonal problems and social hostility in females. Our findings suggest the genetic capacity for microglia function as a potential factor underlying differential susceptibility to early life exposuresthrough influences on neurodevelopment.