Sex differences across developmental domains among children with a familial risk of severe mental disorders.

BACKGROUND: Sex differences in brain structure and neurodevelopment occur in non-clinical populations. We investigated whether sex had a similar effect on developmental domains amongst boys and girls with a familial risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and controls. METHODS: Through Danish registries, we identified 522 7-year-old children (242 girls) with FHR-SZ, FHR-BP, and controls. We assessed their performance within the domains of neurocognition, motor function, language, social cognition, social behavior, psychopathology, and home environment. RESULTS: FHR-SZ boys compared with FHR-SZ girls had a higher proportion of disruptive behavior and attention-deficit hyperactivity disorder (ADHD) and exhibited lower performance in manual dexterity, balance, and emotion recognition. No sex differences were found between boys and girls within FHR-BP group. Compared with controls, both FHR-SZ boys and FHR-SZ girls showed impaired processing speed and working memory, had lower levels of global functioning, and were more likely to live in an inadequate home environment. Compared with control boys, FHR-SZ boys showed impaired manual dexterity, social behavior, and social responsiveness, and had a higher proportion of ADHD and disruptive behavior disorder diagnoses. Stress and adjustment disorders were more common in FHR-BP boys compared with control boys. We found no differences between FHR-BP girls and control girls. CONCLUSIONS: Impairment within neurodevelopmental domains associated within FHR-SZ boys v. FHR-SZ girls was most evident among boys, whereas no sex differences were found within the FHR-BP group (FHR-BP boys v. FHR-BP girls). FHR-SZ boys exhibited the highest proportion of early developmental impairments.

A family-based study of genetic and epigenetic effects across multiple neurocognitive, motor, social-cognitive and social-behavioral functions.

Many psychiatric and neurodevelopmental disorders are known to be heritable, but studies trying to elucidate the genetic architecture of such traits often lag behind studies of somatic traits and diseases. The reasons as to why relatively few genome-wide significant associations have been reported for such traits have to do with the sample sizes needed for the detection of small effects, the difficulty in defining and characterizing the phenotypes, partially due to overlaps in affected underlying domains (which is especially true for cognitive phenotypes), and the complex genetic architectures of the phenotypes, which are not wholly captured in traditional case-control GWAS designs. We aimed to tackle the last two issues by performing GWASs of eight quantitative neurocognitive, motor, social-cognitive and social-behavioral traits, which may be considered endophenotypes for a variety of psychiatric and neurodevelopmental conditions, and for which we employed models capturing both general genetic association and parent-of-origin effects, in a family-based sample comprising 402 children and their parents (mostly family trios). We identified 48 genome-wide significant associations across several traits, of which 3 also survived our strict study-wide quality criteria. We additionally performed a functional annotation of implicated genes, as most of the 48 associations were with variants within protein-coding genes. In total, our study highlighted associations with five genes (TGM3, CACNB4, ANKS1B, CSMD1 and SYNE1) associated with measures of working memory, processing speed and social behavior. Our results thus identify novel associations, including previously unreported parent-of-origin associations with relevant genes, and our top results illustrate new potential gene → endophenotype → disorder pathways.

Association Between Early Risk Factors and Level of Functioning at Age Seven in Children at Familial Risk for Schizophrenia Or Bipolar Disorder - the Danish High Risk and Resilience Study VIA 7.

Background: Facing multiple risk factors, relative to single risk factor exposure early in life can have great implications for negative child development. Objective: We aim to examine whether the prevalence of early risk factors is higher among children with familial high risk for schizophrenia or bipolar disorder compared to controls. Further, to investigate the association between number of early risk factors and level of functioning at age seven, and whether this possible association is different in children with familial high risk compared to controls. Method: The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study of children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) and controls (N = 200). We conducted a semi-structured anamnestic interview with the child's primary caregiver to assess early risk factors from pregnancy to age four. We used the Children's Global Assessment Scale to measure level of functioning at age seven. Results: 13 out of 17 risk factors were more prevalent in children at familial high risk for schizophrenia and 7 out of 17 risk factors were more prevalent in children at familial high risk for bipolar disorder compared to controls. Level of functioning decreased 2.7 (95% CI, 2.2; 3.3)-points per risk factor, but the association was not significantly different across the three groups (p = 0.09). Conclusions: Our results showed that children at age seven with familial high risk for schizophrenia or bipolar disorder experience a greater number of early risk factors. A higher number of early risk factors were associated with lower level of functioning at age seven. However, the association is not different for children with familial high risk or controls.

Genetic assortative mating for schizophrenia and bipolar disorder.

BACKGROUND: Psychiatric disorders are highly polygenic and show patterns of partner resemblance. Partner resemblance has direct population-level genetic implications if it is caused by assortative mating, but not if it is caused by convergence or social homogamy. Using genetics may help distinguish these different mechanisms. Here, we investigated whether partner resemblance for schizophrenia and bipolar disorder is influenced by assortative mating using polygenic risk scores (PRSs). METHODS: PRSs from The Danish High-Risk and Resilience Study-VIA 7 were compared between parents in three subsamples: population-based control parent pairs (N=198), parent pairs where at least one parent had schizophrenia (N=193), and parent pairs where at least one parent had bipolar disorder (N=115). RESULTS: The PRS for schizophrenia was predictive of schizophrenia in the full sample and showed a significant correlation between parent pairs (r=0.121, p=0.0440), indicative of assortative mating. The PRS for bipolar disorder was also correlated between parent pairs (r=0.162, p=0.0067), but it was not predictive of bipolar disorder in the full sample, limiting the interpretation. CONCLUSIONS: Our study provides genetic evidence for assortative mating for schizophrenia, with important implications for our understanding of the genetics of schizophrenia.

Transmission of intelligence, working memory, and processing speed from parents to their seven-year-old offspring is function specific in families with schizophrenia or bipolar disorder.

BACKGROUND: Prior studies have shown high heritability estimates regarding within-function transmission of neurocognition, both in healthy families and in families with schizophrenia but it remains an open question whether transmission from parents to offspring is function specific and whether the pattern is the same in healthy families and families with schizophrenia or bipolar disorder. We aimed to characterize the transmission of intelligence, processing speed, and verbal working memory functions from both biological parents to their 7-year-old offspring in families with parental schizophrenia, bipolar disorder, and population-based control parents. METHODS: The population-based cohort consists of 7-year-old children with one parent diagnosed with schizophrenia (n = 186), bipolar disorder (n = 114), and of parents without schizophrenia or bipolar disorder (n = 192). Children and both parents were assessed using identical, age-relevant neurocognitive tests of intelligence, verbal working memory, and processing speed. RESULTS: In multiple regression analyses children's intelligence, verbal working memory, and processing speed scores were significantly associated with the corresponding parental cognitive function score. All associations from parents to offspring across functions were non-significant. No significant parental cognitive function by group interaction was observed. CONCLUSION: Transmissions of intelligence, processing speed, and verbal working memory from parents to offspring are function specific. The structure of transmission is comparable between families with schizophrenia, families with bipolar disorder and families without these disorders.

Post-error adjustment among children aged 7 years with a familial high risk of schizophrenia or bipolar disorder: A population-based cohort study.

The cognitive control system matures gradually with age and shows age-related sex differences. To gain knowledge concerning error adaptation in familial high-risk groups, investigating error adaptation among the offspring of parents with severe mental disorders is important and may contribute to the understanding of cognitive functioning in at-risk individuals. We identified an observational cohort through Danish registries and measured error adaptation using an Eriksen flanker paradigm. We tested 497 7-year-old children with a familial high risk of schizophrenia (N = 192) or bipolar disorder (N = 116) for deficits in error adaptation compared with a control group (N = 189). We investigated whether error adaptation differed between high-risk groups compared with controls and sex differences in the adaptation to errors, irrespective of high-risk status. Overall, children exhibited post-error slowing (PES), but the slowing of responses did not translate to significant improvements in accuracy. No differences were detected between either high-risk group compared with the controls. Boys showed less PES and PES after incongruent trials than girls. Our results suggest that familial high risk of severe mental disorders does not influence error adaptation at this early stage of cognitive control development. Error adaptation behavior at age 7 years shows specific sex differences.

A Nationwide Cohort Study of Nonrandom Mating in Schizophrenia and Bipolar Disorder.

Nonrandom mating in parents with schizophrenia or bipolar disorder increases the population-level genetic variance among the offspring generation and creates familial (risk) environments likely to be shaped by specific conditions. The objective of this study was to investigate the occurrence of mental disorder and levels of cognitive and social functioning in individuals who have children by partners with schizophrenia or bipolar disorder compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study conducted in Denmark between 2013 and 2016. This study focus on parents diagnosed with schizophrenia (n = 150) or bipolar disorder (n = 100) and control parents (n = 182), as well as their partners without schizophrenia or bipolar disorder (n = 440). We used linear mixed-effect models, and main outcomes were mental disorders, intelligence, processing speed, verbal working memory, and social functioning. We found that parents having children by a partner with schizophrenia or bipolar disorder more often fulfilled the criteria for a mental disorder and had poorer social functioning compared to parents having children by a partner without schizophrenia or bipolar disorder. Furthermore, parents having children by a partner with schizophrenia performed poorer on processing speed compared to parents in the control group. The presence of nonrandom mating found in this study has implications for our understanding of familial transmission of these disorders and our findings should be considered in future investigations of potential risk factors for children with a parent with schizophrenia or bipolar disorder.

An observational study of emotion regulation in children with Tourette syndrome.

BACKGROUND: Explosive outbursts occur in 25%-70% of children with Tourette syndrome (TS) and may cause more distress than the tics themselves. Previous studies have indicated that a comorbid diagnosis of attention-deficit/hyperactivity disorder (ADHD) is associated with emotional dysregulation in TS; however, this relationship has almost exclusively been studied using parent-reported questionnaires. METHODS: We examined emotion regulation (ER) with an observational measure in 150 medication-naïve children aged 7-12 allocated to four groups: Forty-nine children with TS, 23 children with ADHD, 16 children with TS + ADHD, and 62 typically developing controls. We assessed participants' ER ability, as well as parent-child interactions in the context of a complex puzzle task, and coded the observed behavior with the Tangram Emotion Coding Manual (TEC-M). We examined group differences in ER, as well as associations between ER and severity of symptoms pertaining to TS and ADHD. RESULTS: Children with TS did not differ from controls in their ER ability. However, children with ADHD and TS + ADHD had more problems with ER than those with TS only and controls. Finally, parents of children with ADHD displayed more tension during the experimental task. ER ability was not associated with tic severity nor premonitory urges; however, better ER ability was associated with less severe symptoms of ADHD. CONCLUSIONS: This study is the first to evaluate ER with an observational, clinician-rated measure in a controlled social setting in children with TS. Our findings support earlier questionnaire-based studies by showing impaired ER in children with TS + ADHD, but not in children with TS without comorbidity. These findings inform our understanding of the phenomenology of emotional dysregulation in TS and the role of comorbid disorders.

Quantitative genome-wide association analyses of receptive language in the Danish High Risk and Resilience Study.

BACKGROUND: One of the most basic human traits is language. Linguistic ability, and disability, have been shown to have a strong genetic component in family and twin studies, but molecular genetic studies of language phenotypes are scarce, relative to studies of other cognitive traits and neurodevelopmental phenotypes. Moreover, most genetic studies examining such phenotypes do not incorporate parent-of-origin effects, which could account for some of the heritability of the investigated trait. We performed a genome-wide association study of receptive language, examining both child genetic effects and parent-of-origin effects. RESULTS: Using a family-based cohort with 400 children with receptive language scores, we found a genome-wide significant paternal parent-of-origin effect with a SNP, rs11787922, on chromosome 9q21.31, whereby the T allele reduced the mean receptive language score by ~ 23, constituting a reduction of more than 1.5 times the population SD (P = 1.04 × 10-8). We further confirmed that this association was not driven by broader neurodevelopmental diagnoses in the child or a family history of psychiatric diagnoses by incorporating covariates for the above and repeating the analysis. CONCLUSIONS: Our study reports a genome-wide significant association for receptive language skills; to our knowledge, this is the first documented genome-wide significant association for this phenotype. Furthermore, our study illustrates the importance of considering parent-of-origin effects in association studies, particularly in the case of cognitive or neurodevelopmental traits, in which parental genetic data are not always incorporated.

Language deficits in specific language impairment, attention deficit/hyperactivity disorder, and autism spectrum disorder: An analysis of polygenic risk.

Language is one of the cognitive domains often impaired across many neurodevelopmental disorders. While for some disorders the linguistic deficit is the primary impairment (e.g., specific language impairment, SLI), for others it may accompany broader behavioral problems (e.g., autism). The precise nature of this phenotypic overlap has been the subject of debate. Moreover, several studies have found genetic overlaps across neurodevelopmental disorders. This raises the question of whether these genetic overlaps may correlate with phenotypic overlaps and, if so, in what manner. Here, we apply a genome-wide approach to the study of the linguistic deficit in SLI, autism spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Using a discovery genome-wide association study of SLI, we generate polygenic risk scores (PRS) in an independent sample which includes children with language impairment, SLI, ASD or ADHD and age-matched controls and perform regression analyses across groups. The SLI-trained PRS significantly predicted risk in the SLI case-control group (adjusted R2 = 6.24%; P = 0.024) but not in the ASD or ADHD case-control groups (adjusted R2 = 0.0004%, 0.01%; P = 0.984, 0.889, respectively) nor for height, used as a negative control (R2 = 0.2%; P = 0.452). Additionally, there was a significant difference in the normalized PRS between children with SLI and children with ASD (common language effect size = 0.66; P = 0.044). Our study suggests no additive common-variant genetic overlap between SLI and ASD and ADHD. This is discussed in the context of phenotypic studies of SLI and related disorders. Autism Res 2020, 13: 369-381. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Language deficits are characteristic of specific language impairment (SLI), but may also be found in other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Many studies examined the overlaps and differences across the language deficits in these disorders, but few studies have examined the genetic aspect thereof. In this study, we use a genome-wide approach to evaluate whether common genetic variants increasing risk of SLI may also be associated with ASD and ADHD in the same manner. Our results suggest that this is not the case, and we discuss this finding in the context of theories concerning the etiologies of these disorders.

The Puzzle of Emotion Regulation: Development and Evaluation of the Tangram Emotion Coding Manual for Children.

The ability to regulate one's emotions is crucial to engaging successfully in social contexts. Difficulties in emotion regulation are seen in multiple psychiatric disorders, prompting an increased interest in the concept. Suitable methods for assessing emotion regulation, however, are lacking. In this study, we investigated the interrater and intrarater reliability, construct validity, and content validity of a new observational method for evaluating children's emotion regulation abilities (a complex puzzle task) in a sample of 62 children without psychiatric disorders and 23 children with attention-deficit/hyperactivity disorder (ADHD) aged 7-12, using intra-class correlation coefficients for the reliability analyses and Spearman's rank-order correlations for analyses of convergent and discriminant validity. A panel of experts examined the content validity of the test, and Mann-Whitney U-tests were used to investigate the ability of the test to differentiate the non-clinical group from the ADHD group. Results showed a high level of interrater and intrarater reliability of the test. There was mixed evidence for convergent and discriminant validity as expected due to the novelty and experimental nature of the test, making it difficult to compare with questionnaire-based measures. Content validity analysis was satisfactory, and the group comparison showed that the test differentiated the groups on the primary outcome measure. Overall, the measure demonstrated high feasibility and satisfactory psychometric properties. The generic nature of the test makes it suitable for use across psychiatric disorders and age groups with potential relevance in both research and clinical settings.

Social Cognition, Language, and Social Behavior in 7-Year-Old Children at Familial High-Risk of Developing Schizophrenia or Bipolar Disorder: The Danish High Risk and Resilience Study VIA 7-A Population-Based Cohort Study.

OBJECTIVE: To characterize social cognition, language, and social behavior as potentially shared vulnerability markers in children at familial high-risk of schizophrenia (FHR-SZ) and bipolar disorder (FHR-BP). METHODS: The Danish High-Risk and Resilience Study VIA7 is a multisite population-based cohort of 522 7-year-old children extracted from the Danish registries. The population-based controls were matched to the FHR-SZ children on age, sex, and municipality. The FHR-BP group followed same inclusion criteria. Data were collected blinded to familial high-risk status. Outcomes were social cognition, language, and social behavior. RESULTS: The analysis included 202 FHR-SZ children (girls: 46%), 120 FHR-BP children (girls: 46.7%), and 200 controls (girls: 46.5%). FHR-SZ children displayed significant deficits in language (receptive: d = -0.27, P = .006; pragmatic: d = -0.51, P < .001), social responsiveness (d = -0.54, P < .001), and adaptive social functioning (d = -0.47, P < .001) compared to controls after Bonferroni correction. Compared to FHR-BP children, FHR-SZ children performed significantly poorer on adaptive social functioning (d = -0.29, P = .007) after Bonferroni correction. FHR-BP and FHR-SZ children showed no significant social cognitive impairments compared to controls after Bonferroni correction. CONCLUSION: Language, social responsiveness, and adaptive social functioning deficits seem associated with FHR-SZ but not FHR-BP in this developmental phase. The pattern of results suggests adaptive social functioning impairments may not be shared between FHR-BP and FHR-SZ in this developmental phase and thus not reflective of the shared risk factors for schizophrenia and bipolar disorder.

Impairments of motor function among children with a familial risk of schizophrenia or bipolar disorder at 7 years old in Denmark: an observational cohort study.

BACKGROUND: Owing to the genetic overlap between schizophrenia and bipolar disorder, we aimed to assess domain-specific motor aberrations and disorder specificity among 7-year-old children with a familial risk of schizophrenia or bipolar disorder by comparing children in familial risk groups with each other and with children not in these risk groups. METHODS: In the Danish High Risk and Resilience Study, we established a cohort of 7-year-old children with no, one, or two parents with schizophrenia or bipolar disorder in Denmark between Jan 1, 2013, and Jan 31, 2016. We matched children of parents diagnosed with schizophrenia to children of parents without schizophrenia on the basis of their home address, age, and sex. Even though we did not match children of parents with bipolar disorder directly to controls because of resource constraints, we only recruited children into the three groups who did not differ in terms of age, sex, and urbanicity. We investigated motor function in children using the Movement Assessment Battery for Children-Second Edition. Motor function raters were masked to participants' clinical risk status during assessments. We assessed the effects of familial risk group in a mixed-model analysis with repeated measures with an unstructured variance component matrix. FINDINGS: We studied 514 children (198 [39%] children of parents with schizophrenia, 119 [23%] of parents with bipolar disorder, and 197 [38%] of parents without schizophrenia or bipolar disorder). Children of parents with schizophrenia showed impaired motor performance compared with those of parents without in the subdomains of manual dexterity (mean difference -1·42 [95% CI -2·08 to -0·77]; p<0·0001) and balance (-1·38 [-2·03 to -0·72]; p<0·0001), but not of aiming and catching (-0·39 [-0·97 to 0·19]; p=0·18). Children of parents with bipolar disorder did not show any significant difference in motor performance to children of parents without in the subdomains of manual dexterity (-0·69 [-1·44 to 0·07]; p=0·08), balance (-0·68 [-1·44 to 0·08]; p=0·08), and aiming and catching (-0·36 [-1·03 to 0·31]; p=0·29). Comparison of familial risk groups of mental disorders revealed no significant differences in the subdomains of manual dexterity (-0·74 [-1·49 to 0·02]; p=0·06), balance (-0·70 [-1·46 to 0·06]; p=0·07), or aiming and catching (-0·03 [-0·70 to 0·63]; p=0·92). INTERPRETATION: Motor abnormalities in children with a familial risk of schizophrenia are specific at 7 years of age with respect to fine motor function and balance, but non-specific with respect to familial risk of bipolar disorder. Clinicians should be aware of motor symptoms and refer children with definite motor problems (below the fifth percentile) to a child physiotherapist. FUNDING: Mental Health Services of the Capital Region of Denmark, Aarhus University, and the Lundbeck Foundation Initiative for Integrative Psychiatric Research.