Quality control and analytic best practices for testing genetic models of sex differences in large populations.

Phenotypic sex-based differences exist for many complex traits. In other cases, phenotypes may be similar, but underlying biology may vary. Thus, sex-aware genetic analyses are becoming increasingly important for understanding the mechanisms driving these differences. To this end, we provide a guide outlining the current best practices for testing various models of sex-dependent genetic effects in complex traits and disease conditions, noting that this is an evolving field. Insights from sex-aware analyses will not only teach us about the biology of complex traits but also aid in achieving the goals of precision medicine and health equity for all.

Estimating the impact of transmitted and non-transmitted psychiatric and neurodevelopmental polygenic scores on youth emotional problems.

Anxiety and depression (emotional disorders) are familial and heritable, especially when onset is early. However, other cross-generational studies suggest transmission of youth emotional problems is explained by mainly environmental risks. We set out to test the contribution of parental non-transmitted genetic liability, as indexed by psychiatric/neurodevelopmental common polygenic liability, to youth emotional problems using a UK population-based cohort: the Millennium Cohort Study. European (N = 6328) and South Asian (N = 814) ancestries were included, as well as a subset with genomic data from both parents (European: N = 2809; South Asian: N = 254). We examined the association of transmitted (PGST) and non-transmitted polygenic scores (PGSNT) for anxiety, depression, bipolar disorder and neurodevelopmental disorders (attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD], schizophrenia) with youth emotional disorder and symptom scores, measured using the parent- and self-reported Strengths and Difficulties Questionnaire emotional subscale at 6 timepoints between ages 3-17 years. In the European sample, PGST for anxiety and depression, but not bipolar disorder, were associated with emotional disorder and symptom scores across all ages, except age 3, with strongest association in adolescence. ADHD and ASD PGST also showed association across ages 11-17 years. In the South Asian sample, evidence for associations between all PGST and outcome measures were weaker. There was weak evidence of association between PGSNT for anxiety and depression and age 17 symptom scores in the South Asian sample, but not in the European sample for any outcome. Overall, PGST for depression, anxiety, ADHD and ASD contributed to youth emotional problems, with stronger associations in adolescence. There was limited support for non-transmitted genetic effects: these findings do not support the hypothesis that parental polygenic psychiatric/neurodevelopmental liability confer risk to offspring emotional problems through non-transmitted rearing/nurture effects.

Sex differences in attention-deficit hyperactivity disorder diagnosis and clinical care: a national study of population healthcare records in Wales.

BACKGROUND: Population-based studies have observed sex biases in the diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD). Females are less likely to be diagnosed or prescribed ADHD medication. This study uses national healthcare records, to investigate sex differences in diagnosis and clinical care in young people with ADHD, particularly regarding recognition and treatment of other mental health conditions. METHODS: The cohort included individuals diagnosed with ADHD, born between 1989 and 2013 and living in Wales between 2000 and 2019. Routine primary and secondary healthcare record data were used to derive diagnoses of ADHD and other neurodevelopmental and mental health conditions, as well as ADHD and antidepressant medications. Demographic variables included ethnicity, socioeconomic deprivation and contact with social services. RESULTS: There were 16,458 individuals diagnosed with ADHD (20.3% females, ages 3-30 years), with a male-to-female ratio of 3.9:1. Higher ratios (4.8:1) were seen in individuals diagnosed younger (<12 years), with the lowest ratio (1.9:1) in those diagnosed as adults (>18). Males were younger at first recorded ADHD diagnosis (mean = 10.9 vs. 12.6 years), more likely to be prescribed ADHD medication and younger at diagnosis of co-occurring neurodevelopmental conditions. In contrast, females were more likely to receive a diagnosis of anxiety, depression or another mental health condition and to be prescribed antidepressant medications, prior to ADHD diagnosis. These sex differences were largely stable across demographic groups. CONCLUSIONS: This study adds to the evidence base that females with ADHD are experiencing later recognition and treatment of ADHD. The results indicate that this may be partly because of diagnostic overshadowing from other mental health conditions, such as anxiety and depression, or initial misdiagnosis. Further research and dissemination of findings to the public are needed to improve awareness, timely diagnosis and treatment of ADHD in females.

Stratifying early-onset emotional disorders: using genetics to assess persistence in young people of European and South Asian ancestry.

BACKGROUND: Depression and anxiety are the most common mental health problems in young people. Currently, clinicians are advised to wait before initiating treatment for young people with these disorders as many spontaneously remit. However, others develop recurrent disorder but this subgroup cannot be identified at the outset. We examined whether psychiatric polygenic scores (PGS) could help inform stratification efforts to predict those at higher risk of recurrence. METHODS: Probable emotional disorder was examined in two UK population cohorts using the emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ). Those with emotional disorder at two or more time points between ages 5 and 25 years were classed as 'recurrent emotional disorder' (n = 1,643) and those with emotional disorder at one time point as having 'single episode emotional disorder' (n = 1,435, controls n = 8,715). We first examined the relationship between psychiatric PGS and emotional disorders in childhood and adolescence. Second, we tested whether psychiatric PGS added to predictor variables of known association with emotional disorder (neurodevelopmental comorbidity, special educational needs, family history of depression and socioeconomic status) when discriminating between single-episode and recurrent emotional disorder. Analyses were conducted separately in individuals of European and South Asian ancestry. RESULTS: Probable emotional disorder was associated with higher PGS for major depressive disorder (MDD), anxiety, broad depression, ADHD and autism spectrum disorder (ASD) in those of European ancestry. Higher MDD and broad depression PGS were associated with emotional disorder in people of South Asian ancestry. Recurrent, compared to single-episode, emotional disorder was associated with ASD and parental psychiatric history. PGS were not associated with episode recurrence, and PGS did not improve discrimination of recurrence when combined with clinical predictors. CONCLUSIONS: Our findings do not support the use of PGS as a tool to assess the likelihood of recurrence in young people experiencing their first episode of emotional disorder.

Emotional problems across development: examining measurement invariance across childhood, adolescence and early adulthood.

Emotional problems (anxiety, depression) are prevalent in children, adolescents and young adults with varying ages at onset. Studying developmental changes in emotional problems requires repeated assessments using the same or equivalent measures. The parent-rated Strengths and Difficulties Questionnaire is commonly used to assess emotional problems in childhood and adolescence, but there is limited research about whether it captures a similar construct across these developmental periods. Our study addressed this by investigating measurement invariance in the scales' emotional problems subscale (SDQ-EP) across childhood, adolescence and early adulthood. Data from two UK population cohorts were utilised: the Millennium Cohort Study (ages 3-17 years) and the Avon Longitudinal Study of Parents and Children (4-25 years). In both samples we observed weak (metric) measurement invariance by age, suggesting that the parent-rated SDQ-EP items contribute to the underlying construct of emotional problems similarly across age. This supports the validity of using the subscale to rank participants on their levels of emotional problems in childhood, adolescence and early adulthood. However strong (scalar) measurement invariance was not observed, suggesting that the same score may correspond to different levels of emotional problems across developmental periods. Comparisons of mean parent-rated SDQ-EP scores across age may therefore not be valid.

A twin study of genetic and environmental contributions to attention-deficit/hyperactivity disorder over time.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is an increasingly commonly diagnosed neurodevelopmental condition. One possibility is that this reflects a genuine increase in the prevalence of ADHD due to secular environmental changes, yet this hypothesis remains untested. We therefore investigated whether the genetic and environmental variance underlying ADHD, and traits of ADHD, has changed over time. METHODS: We identified twins born from 1982 to 2008 from the Swedish Twin Registry (STR). We linked the STR with the Swedish National Patient Register and Prescribed Drug Register to identify diagnoses of ADHD and prescriptions of ADHD medication for these twins. We also utilized data collected from participants in the Child and Adolescent Twin Study in Sweden (CATSS), born from 1992 to 2008. Their parents completed a structured ADHD screening tool, which was used to measure traits of ADHD and assign broad screening diagnoses of ADHD. We used the classical twin design to test whether the degree to which variation in these measures was influenced by genetic and environmental variation changed over time. RESULTS: We included 22,678 twin pairs from the STR and 15,036 pairs from CATSS. The heritability of ADHD in the STR ranged from 66% to 86% over time, although these fluctuations were not statistically significant. We observed a modest increase in variance in ADHD traits, from 0.98 to 1.09. This was driven by small increases in the underlying genetic and environmental variance, with heritability estimated as 64%-65%. No statistically significant changes in variance in screening diagnoses were observed. CONCLUSIONS: The relative contribution of genetic and environmental factors to ADHD has remained stable over time, despite its increasing prevalence. Thus, changes in the underlying etiology of ADHD over time are unlikely to explain the increase in ADHD diagnoses.

Sleep disturbances in ADHD: investigating the contribution of polygenic liability for ADHD and sleep-related phenotypes.

Sleep disturbances are common in attention deficit hyperactivity disorder (ADHD) and associated with poor outcomes. We tested whether, in children with ADHD, (1) polygenic liability for sleep phenotypes is over- or under-transmitted from parents, (2) this liability is linked to comorbid sleep disturbances, and (3) ADHD genetic risk is associated with comorbid sleep disturbances. We derived polygenic scores (PGS) for insomnia, chronotype, sleep duration, and ADHD, in 758 children (5-18 years old) diagnosed with ADHD and their parents. We conducted polygenic transmission disequilibrium tests for each sleep PGS in complete parent-offspring ADHD trios (N = 328) and an independent replication sample of ADHD trios (N = 844). Next, we tested whether insomnia, sleep duration, and ADHD PGS were associated with co-occurring sleep phenotypes (hypersomnia, insomnia, restless sleep, poor sleep quality, and nightmares) in children with ADHD. Children's insomnia and chronotype PGS did not differ from mid-parent average PGS but long sleep duration PGS were significantly over-transmitted to children with ADHD. This was supported by a combined analysis using the replication sample. Insomnia, sleep duration, and ADHD PGS were not associated with comorbid sleep disturbances. There is weak evidence that children with ADHD over-inherit polygenic liability for longer sleep duration and do not differentially inherit polygenic liability for insomnia or chronotype. There was insufficient evidence that childhood sleep disturbances were driven by polygenic liability for ADHD or sleep traits, suggesting that sleep disturbances in ADHD may be aetiologically different to general population sleep phenotypes and do not index greater ADHD genetic risk burden.

An agenda for future research regarding the mental health of young people with care experience.

Young people who are currently or were previously in state care have consistently been found to have much higher rates of mental health and neurodevelopmental difficulties than the general youth population. While a number of high-quality reviews highlight what research has been undertaken in relation to the mental health of young people with care experience and the gaps in our knowledge and understanding, there is, until now, no consensus, so far as we aware, as to where our collective research efforts should be directed with this important group. Through a series of UK wide workshops, we undertook a consultative process to identify an agreed research agenda between those with lived experience of being in care (n = 15), practitioners, policy makers and researchers (n = 59), for future research regarding the mental health of young people with care experience, including those who are neurodiverse/have a neurodevelopmental difficulty. This consensus statement identified 21 foci within four broad categories: how we conceptualize mental health; under-studied populations; under-studied topics; and underused methodologies. We hope that those who commission, fund and undertake research will engage in this discussion about the future agenda for research regarding the mental health of young people with care experience.

Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). METHODS: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

Insights into attention-deficit/hyperactivity disorder from recent genetic studies.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder (NDD). In this narrative review, we summarize recent advances in quantitative and molecular genetic research from the past 5-10 years. Combined with large-scale international collaboration, these advances have resulted in fast-paced progress in understanding the etiology of ADHD and how genetic risk factors map on to clinical heterogeneity. Studies are converging on a number of key insights. First, ADHD is a highly polygenic NDD with a complex genetic architecture encompassing risk variants across the spectrum of allelic frequencies, which are implicated in neurobiological processes. Second, genetic studies strongly suggest that ADHD diagnosis shares a large proportion of genetic risks with continuously distributed traits of ADHD in the population, with shared genetic risks also seen across development and sex. Third, ADHD genetic risks are shared with those implicated in many other neurodevelopmental, psychiatric and somatic phenotypes. As sample sizes and the diversity of genetic studies continue to increase through international collaborative efforts, we anticipate further success with gene discovery, characterization of how the ADHD phenotype relates to other human traits and growing potential to use genomic risk factors for understanding clinical trajectories and for precision medicine approaches.

Examining the association between childhood autistic traits and adolescent hypomania: a longitudinal twin study.

BACKGROUND: There is evidence that autism spectrum disorders (ASDs) co-occur with bipolar disorder (BD) relatively frequently. Individuals with BD often report symptoms of mania and hypomania during adolescence, prior to the age of onset for BD. It is unknown whether these symptoms are associated with ASDs. We examined whether diagnoses of ASDs and autistic traits were associated with hypomania in a large, population-based Swedish twin sample. METHODS: Parental structured interviews assessed autistic traits, and were used to assign screening diagnoses of ASDs, when twins were aged 9 or 12 (N = 13 533 pairs). Parents then completed questionnaires assessing hypomania when the twins were aged 15 and 18 (N = 3852 pairs at age 15, and 3013 pairs at age 18). After investigating the phenotypic associations between these measures, we used the classical twin design to test whether genetic and environmental influences on autistic traits influence variation in adolescent hypomania. RESULTS: Autistic traits and ASD diagnoses in childhood were associated with elevated scores on the measures of adolescent hypomania. Twin analyses indicated that 6-9% of the variance in hypomania was explained by genetic influences that were shared with autistic traits in childhood. When repeating these analyses for specific autistic trait domains, we found a stronger association between social interaction difficulties and hypomania than for other autistic trait domains. CONCLUSIONS: These results indicate a genetic link between autistic traits and hypomania in adolescence. This adds to the growing evidence base of genetic factors associated with ASDs showing links with psychiatric outcomes across childhood and into adulthood.

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology.

Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R2 = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

Familial and genetic associations between autism spectrum disorder and other neurodevelopmental and psychiatric disorders.

BACKGROUND: Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. METHODS: Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp ) and genetic associations (rg ), as well as the contribution of genetic influences to rp . RESULTS: The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg  = 0.73; 95% CI = 0.66-0.79). Moderate genetic correlations were estimated for anxiety disorders (rg  = 0.47; 95% CI = 0.33-0.61), depression (rg  = 0.52; 95% CI = 0.37-0.66), and intentional self-harm (rg  = 0.54; 95% CI = 0.36-0.71). CONCLUSIONS: ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.

Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity.

It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.

Using Genetics to Examine a General Liability to Childhood Psychopathology.

Psychiatric disorders show phenotypic as well as genetic overlaps. There are however also marked developmental changes throughout childhood. We investigated the extent to which, for a full range of early childhood psychopathology, a general "p" factor was explained by genetic liability, as indexed by multiple different psychiatric polygenic risk scores (PRS) and whether these relationships altered with age. The sample was a UK, prospective, population-based cohort with psychopathology data at age 7 (N = 8161) and age 13 (N = 7017). PRS were generated from large published genome-wide association studies. At both ages, we found evidence for a childhood "p" factor as well as for specific factors. Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) PRS were associated with this general "p" factor at both ages but depression and autism spectrum disorder (ASD) PRS were not. We also found some evidence of associations between schizophrenia, ADHD and depression PRS with specific factors, but these were less robust and there was evidence for developmental changes.

Meeting the guidelines: Implementing a distress screening intervention for veterans with cancer.

BACKGROUND: Guidelines recommend systematic evaluation of distress screening and referral for cancer patients. Implementation remains a notable gap for cancer centers serving disadvantaged communities. We present the implementation of a distress screening program within a Veterans Affairs hospital oncology clinic, serving a majority African American (AA) male population of low socioeconomic status (SES). METHODS: The Coleman Foundation funded this program supporting a palliative care physician and psychologist to implement screening in a phased approach as follows: (1) Organizing key stakeholders, (2) educating clinical staff, (3) delivering distress screening, (4) generating documentation, and (5) implementing clinical action and referral pathways. We utilized validated measures in the "Patient Screening Questions for Supportive Care" screening tool. RESULTS: This program was unsuccessful in screening all veterans with cancer; however, we were able to implement 3 years of longitudinal screening. In distress screens from the initial program period (n = 253), patients were primarily males (95.6%) of older age (m = 70, standard deviation = 9.45), AA (76.4%), with various cancers of advanced disease (69%). Males reported moderate psychosocial distress and elevated financial needs. For males with elevated psychosocial distress (n = 63, PHQ-4 ≥3), 36% were previously connected with psychosocial services. Following screening, engagement increased as the majority (77%) established psychosocial care. CONCLUSIONS: This screening program had mixed success. Centralized program staff and available supportive care referrals were critical for program implementation. Screening may have increased engagement in social work/mental health services for males of low SES. Screening programs should be tailored to the needs of underserved communities with accessible housing/food subsidies.

What explains the link between childhood ADHD and adolescent depression? Investigating the role of peer relationships and academic attainment.

There is increasing evidence that childhood Attention-Deficit Hyperactivity Disorder (ADHD) elevates risk of later depression, but the mechanisms behind this association are unclear. We investigated the relationship between childhood ADHD symptoms and late-adolescent depressive symptoms in a population cohort, and examined whether academic attainment and peer problems mediated this association. ALSPAC (Avon Longitudinal Study of Parents and Children) is an ongoing prospective longitudinal population-based UK cohort that has collected data since September 1990. 2950 individuals with data on parent-reported ADHD symptoms in childhood (7.5 years) and self-reported depressive symptoms in late adolescence (17.5 years) were included in analyses. 2161 individuals with additional data at age 16 years on parent-reported peer problems as an indicator of peer relationships and formal examination results (General Certificate of Secondary Education; GCSE) as an indicator of academic attainment were included in mediation analyses. Childhood ADHD symptoms were associated with higher depressive symptoms (b = 0.49, SE = 0.11, p < 0.001) and an increased odds of clinically significant depressive symptoms in adolescence (OR = 1.27, 95% CI 1.15-1.41, p < 0.001). The association with depressive symptoms was mediated in part by peer problems and academic attainment which accounted for 14.68% and 20.13% of the total effect, respectively. Childhood ADHD is associated with increased risk of later depression. The relationship is mediated in part by peer relationships and academic attainment. This highlights peer relationships and academic attainment as potential targets of depression prevention and intervention in those with ADHD. Future research should investigate which aspects of peer relationships are important in conferring later risk for depression.

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

Sex differences in predicting ADHD clinical diagnosis and pharmacological treatment.

In youth, ADHD is more commonly diagnosed in males than females, but higher male-to-female ratios are found in clinical versus population-based samples, suggesting a sex bias in the process of receiving a clinical diagnosis of ADHD. This study investigated sex differences in the severity and presentation of ADHD symptoms, conduct problems, and learning problems in males and females with and without clinically diagnosed ADHD. We then investigated whether the predictive associations of these symptom domains on being diagnosed and treated for ADHD differed in males and females. Parents of 19,804 twins (50.64% male) from the Swedish population completed dimensional assessments of ADHD symptoms and co-occurring traits (conduct and learning problems) when children were aged 9 years. Children from this population sample were linked to Patient Register data on clinical ADHD diagnosis and medication prescriptions. At the population level, males had higher scores for all symptom domains (inattention, hyperactivity/impulsivity, conduct, and learning problems) compared to females, but similar severity was seen in clinically diagnosed males and females. Symptom severity for all domains increased the likelihood of receiving an ADHD diagnosis in both males and females. Prediction analyses revealed significant sex-by-symptom interactions on diagnostic and treatment status for hyperactivity/impulsivity and conduct problems. In females, these behaviours were stronger predictors of clinical diagnosis (hyperactivity/impulsivity: OR 1.08, 95% CI 1.01, 1.15; conduct: OR 1.43, 95% CI 1.09, 1.87), and prescription of pharmacological treatment (hyperactivity/impulsivity: OR 1.24, 95% CI 1.02, 1.50; conduct: OR 2.20, 95% CI 1.05, 4.63). Females with ADHD may be more easily missed in the ADHD diagnostic process and less likely to be prescribed medication unless they have prominent externalising problems.

Copy number variation and neuropsychiatric problems in females and males in the general population.

Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex-specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorized by size (100-500 kb or > 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex-specific effects. Medium deletions (OR[CI] = 1.18[1.05-1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19-1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14-3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45-9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.