Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

A structural variation reference for medical and population genetics.

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

Caffeine Use and Associations With Sleep in Adolescents With and Without ADHD.

OBJECTIVE: The objective of this study was to compare caffeine consumption in the morning, afternoon, and evening in adolescents with and without attention-deficit/hyperactivity disorder (ADHD) and examine associations with sleep functioning. METHODS: Participants were 302 adolescents (ages 12-14) with (N = 140) and without (N = 162) ADHD. Adolescents wore actigraph watches to assess total sleep time and wake after sleep onset and reported on sleep-wake problems and the number of caffeinated beverages consumed per day in the morning, afternoon, and evening. Parents reported on adolescents' difficulties initiating and maintaining sleep. Chi-square tests, odds ratios, and path analyses were conducted. RESULTS: Analyses controlled for sex, medication status, and pubertal development. Adolescents with ADHD were 2.47 times more likely to consume caffeine in the afternoon and evening than adolescents without ADHD. Path analyses indicated significant associations between afternoon caffeine use and more self-reported sleep problems for adolescents with and without ADHD, and an association between evening caffeine use and self-reported sleep problems only in adolescents with ADHD. Afternoon caffeine use was associated with parent-reported sleep problems in adolescents with ADHD only. Caffeine use was not associated with actigraphy-assessed sleep. CONCLUSION: This is the first study to show that adolescents with ADHD consume more caffeine than peers during later times of the day. Additionally, caffeine use is more consistently associated with poorer subjective sleep functioning in adolescents with ADHD. Pediatricians and mental health professionals should assess for caffeine use in adolescents with ADHD and co-occurring sleep problems.

Intraindividual variability of sleep/wake patterns in adolescents with and without attention-deficit/hyperactivity disorder.

BACKGROUND: Prior studies examining the sleep of adolescents with and without attention-deficit/hyperactivity disorder (ADHD) have relied on mean values such as average sleep duration, which masks intraindividual variability (IIV). The objective was to investigate whether adolescents with ADHD have greater IIV of sleep/wake patterns than adolescents without ADHD using actigraphy and daily sleep diaries. METHOD: Adolescents (ages 13.17 ± 0.40 years; 45% female) with (n = 162) and without (n = 140) ADHD were recruited from middle schools at two sites. Participants wore actigraphs and completed sleep diaries for an average of 2 weeks. RESULTS: Multilevel models were conducted with sex, sleep medication use, ADHD medication use, number of days with data, and social jetlag controlled for in analyses. For actigraphy, adolescents with ADHD had greater variability for time in bed, sleep onset and offset, and wake after sleep onset than adolescents without ADHD. For sleep diary data, adolescents with ADHD had greater variability in bedtime, wake time, sleep duration, sleep onset latency, sleep quality, and night wakings than adolescents without ADHD. Social jetlag was a significant predictor of variability in sleep measures based on both actigraph and daily diaries; however, ADHD status was not associated with social jetlag. CONCLUSIONS: This is the first study to show that adolescents with ADHD have more variable sleep/wake patterns than their peers using both objective and subjective sleep measures. IIV of sleep/wake patterns may be important for clinicians to assess and monitor as part of treatment. Research is needed to understand the mechanisms underlying increased IIV of sleep/wake patterns in adolescents with ADHD and potential consequences for daytime functioning.

Featured Article: Technology Use and Sleep in Adolescents With and Without Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: This study used a multi-informant approach to examine differences in types and rates of technology used by adolescents with and without attention-deficit/hyperactivity disorder (ADHD), associations between technology use and sleep/daytime sleepiness, and whether technology use was differentially related to sleep/daytime sleepiness in adolescents with and without ADHD. METHODS: Eighth graders with (n = 162) and without (n = 140) ADHD were recruited. Adolescents completed questionnaires assessing time spent using technology, sleep-wake problems, school-night time in bed, and daytime sleepiness. Parents and teachers reported on adolescents' technology use and daytime sleepiness, respectively. RESULTS: Adolescents with ADHD had significantly greater total technology, television/movie viewing, video game, and phone/video chatting use than adolescents without ADHD. Adolescents with ADHD engaged in twice as much daily video game use compared to those without ADHD (61 vs. 31 min). Controlling for medication use, ADHD status, pubertal development, sex, and internalizing symptoms, greater parent- and adolescent-reported technology use was associated with more sleep-wake problems and less time in bed. ADHD status did not moderate the relations between technology use and these sleep parameters. In contrast, ADHD status moderated the association between parent-reported technology use and teacher-reported daytime sleepiness, such that this association was significant only for adolescents with ADHD. CONCLUSIONS: Technology use, although more prevalent in adolescents with ADHD, is linked with more sleep problems and reduced school-night sleep duration regardless of ADHD status. Technology use is associated with teacher-rated daytime sleepiness only in adolescents with ADHD. Clinicians should consider technology usage when assessing and treating sleep problems.

The impact of comorbid mental health symptoms and sex on sleep functioning in children with ADHD.

Children with attention-deficit/hyperactivity disorder (ADHD) display more sleep problems than their peers, but it remains unclear whether comorbid mental health symptoms [i.e., anxiety, depression, oppositional-defiant disorder (ODD)] are uniquely related to sleep functioning. It is also largely unknown whether boys and girls with ADHD differ in their sleep functioning. This study (1) examined whether boys or girls with ADHD differ in their sleep functioning, (2) evaluated comorbid symptoms as uniquely related to sleep functioning domains, and (3) explored whether sex moderated associations between comorbid symptoms and sleep. Participants were 181 children (ages 7-13; 69% male; 82% White) diagnosed with ADHD. Parents completed measures assessing their child's ADHD symptoms, comorbid symptoms, and sleep functioning. Girls had poorer sleep functioning than boys across most sleep functioning domains. Sixty percent of children met cutoff criteria for having sleep problems, though rates differed significantly between girls (75%) and boys (53%). No differences in rates of sleep problems were found between ADHD subtypes/presentations or between younger and older children. In path models including ADHD and comorbid symptom dimensions, anxiety symptoms were uniquely associated with increased bedtime resistance and sleep anxiety, ADHD hyperactive-impulsive symptoms were associated with more night wakings and more parasomnia behaviors, and ODD and depressive symptoms were associated with shorter sleep duration. Depression was also uniquely associated with increased daytime sleepiness and overall sleep problems. Sex did not moderate associations between comorbid symptoms and sleep problems. This study provides important preliminary evidence that girls with ADHD experience more sleep problems than boys with ADHD. Findings also demonstrate that the associations between comorbid symptoms and sleep functioning in children with ADHD vary based on both the specific symptoms and sleep domains examined.

Principled distillation of UK Biobank phenotype data reveals underlying structure in human variation.

Data within biobanks capture broad yet detailed indices of human variation, but biobank-wide insights can be difficult to extract due to complexity and scale. Here, using large-scale factor analysis, we distill hundreds of variables (diagnoses, assessments and survey items) into 35 latent constructs, using data from unrelated individuals with predominantly estimated European genetic ancestry in UK Biobank. These factors recapitulate known disease classifications, disentangle elements of socioeconomic status, highlight the relevance of psychiatric constructs to health and improve measurement of pro-health behaviours. We go on to demonstrate the power of this approach to clarify genetic signal, enhance discovery and identify associations between underlying phenotypic structure and health outcomes. In building a deeper understanding of ways in which constructs such as socioeconomic status, trauma, or physical activity are structured in the dataset, we emphasize the importance of considering the interwoven nature of the human phenome when evaluating public health patterns.

COVID-19 Resulted in Lower Grades for Male High School Students and Students With ADHD.

OBJECTIVE: Researchers have speculated that the COVID-19 pandemic may expand the academic performance gap experienced by at-risk students. We examined learning experiences during the 2020 to 2021 school year and the impact the pandemic has had on high school student grade point average (GPA), including predictors of change in GPA from 2019-2020 to 2020-2021. METHOD: Participants were 238 adolescents (55.5% male), 49.6% with attention-deficit/hyperactivity disorder (ADHD), in the United States. Adolescents reported on their GPAs via online surveys. RESULTS: GPA significantly decreased on average from 2019-2020 to 2020-2021 school year. ADHD status and biological sex significantly moderated change-students with ADHD and male students reported decreased GPA, whereas students without ADHD and female students' GPA did not change. Low income and Black/Latinx students had lower GPAs in both school years. CONCLUSION: It is imperative that additional supports be provided for at-risk students to help them catch up on missed learning during the pandemic.

Coping with COVID-19: Longitudinal Impact of the Pandemic on Adjustment and Links with Coping for Adolescents with and without ADHD.

Understanding factors that foster resilience and buffer against the negative psychological impact of COVID-19 is critical to inform efforts to promote adjustment, reduce risk, and improve care, particularly for adolescents with neurodevelopmental disorders. This prospective longitudinal study addresses this gap by investigating the impact of the COVID-19 pandemic on adolescents' mental health and substance use, and by assessing specific positive coping strategies among adolescents with and without attention-deficit/hyperactivity disorder (ADHD). Using multi-group autoregressive cross-lagged path models, the present study explored the reciprocal influence of positive coping behaviors on multiple adjustment outcomes including mental health symptoms, substance use, stress, and worry. Participants included 238 adolescents (132 male participants; ages 15-17; 118 with ADHD). Parents provided ratings of adolescent routines, and adolescents provided ratings of coping behaviors and psychological adjustment in spring (May/June), summer (July/August), and fall (October/November) 2020. All models included the effects of adjustment at the prior timepoint as well as relevant covariates including adolescent race, ethnicity, sex, medication status, and family income. Adolescents with ADHD were at greater risk for experiencing increases in mental health symptoms and substance use throughout the pandemic, relative to adolescents without ADHD. The use of positive coping strategies and adolescent routines buffered against increases in substance use and mental health problems for adolescents with ADHD. These findings have important clinical and public policy relevance for parents, schools, and employers who may aim to prioritize keeping schedules as consistent as possible to promote healthy adjustment.

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism.

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

Prospective examination of adolescent sleep patterns and behaviors before and during COVID-19.

STUDY OBJECTIVES: To prospectively examine changes in adolescent sleep before and during the COVID-19 pandemic in adolescents with and without ADHD. METHODS: Participants were 122 adolescents (ages 15-17; 61% male; 48% with ADHD). Parents reported on adolescents' sleep duration and difficulties initiating and maintaining sleep (DIMS); adolescents reported on sleep patterns, sleep duration, delayed sleep/wake behaviors, and daytime sleepiness before (September 2019 to February 2020) and during (May-June 2020) COVID-19. Adolescents also reported on their health behaviors, COVID-19-related negative affect, and difficulties concentrating due to COVID-19. RESULTS: Parents reported adolescents had more DIMS during COVID-19 than before COVID-19, with clinically elevated rates increasing from 24% to 36%. Both bedtimes and waketimes shifted later during COVID-19, and adolescents reported more delayed sleep/wake behaviors. Adolescents also reported less daytime sleepiness and longer school night sleep duration during COVID-19. In considering differences between adolescents with and without ADHD, adolescents with ADHD did not experience an increase in school night sleep duration and were less likely to obtain recommended sleep duration during COVID-19. In the full sample, controlling for ADHD status, COVID-19-related sadness/loneliness was associated with increases in DIMS, and spending less time outside and more COVID-19-related worries/fears were associated with increases in delayed sleep/wake behaviors during COVID-19. CONCLUSIONS: COVID-19 had negative and positive impacts on adolescent sleep. Adolescents with ADHD did not experience the benefit of increased school night sleep duration during COVID-19 like adolescents without ADHD. Negative affect and health behaviors may be useful intervention targets for reducing negative impacts of COVID-19 for adolescent sleep.

Phylogenetic analysis of SARS-CoV-2 in Boston highlights the impact of superspreading events.

Analysis of 772 complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from early in the Boston-area epidemic revealed numerous introductions of the virus, a small number of which led to most cases. The data revealed two superspreading events. One, in a skilled nursing facility, led to rapid transmission and significant mortality in this vulnerable population but little broader spread, whereas other introductions into the facility had little effect. The second, at an international business conference, produced sustained community transmission and was exported, resulting in extensive regional, national, and international spread. The two events also differed substantially in the genetic variation they generated, suggesting varying transmission dynamics in superspreading events. Our results show how genomic epidemiology can help to understand the link between individual clusters and wider community spread.

Academic Motivation Deficits in Adolescents with ADHD and Associations with Academic Functioning.

The present study evaluates differences in self-reported intrinsic and extrinsic academic motivation and amotivation between eighth-grade adolescents with (n = 162) and without (n = 140) ADHD. This study also examines associations between motivation and academic functioning with objective (i.e., grade point average, standardized reading and math scores) and cross-rater measurement (i.e., parent-reported homework performance). Multivariate analysis of variance controlling for sex, intelligence, and medication status found that adolescents with ADHD exhibited a significant motivational deficit compared to adolescents without ADHD across all areas of academic motivation, including intrinsic motivation (d = 0.49), extrinsic motivation (d = 0.43), and amotivation (d = 0.42). To examine whether motivation was differentially associated with academic impairment in the ADHD and comparison groups, a multi-group path analysis was conducted controlling for sex, intelligence, and medication status. Findings showed that motivation was differentially associated with academic impairment for adolescents with and without ADHD. For the comparison group, higher amotivation was associated with poorer homework performance and lower intrinsic motivation was associated with lower reading accuracy. In the ADHD group, higher amotivation was associated with poorer homework performance and math fluency, higher extrinsic motivation was associated with better homework performance and higher GPA, and higher intrinsic motivation was associated with higher reading accuracy. This study builds upon previous research in demonstrating that adolescents with ADHD have academic motivational deficits when compared to their peers without ADHD. Research is needed to understand the longitudinal interplay of academic motivation and academic functioning, with an eye towards developing or modifying interventions to increase academic motivation and academic success.

Remote Learning During COVID-19: Examining School Practices, Service Continuation, and Difficulties for Adolescents With and Without Attention-Deficit/Hyperactivity Disorder.

PURPOSE: This study examined remote learning practices and difficulties during initial stay-at-home orders during the COVID-19 pandemic in adolescents with and without attention-deficit/hyperactivity disorder (ADHD). METHODS: Participants were 238 adolescents (132 males; 118 with ADHD) aged 15.64-17.99 years and their parents. Adolescents and parents completed questionnaires in May/June 2020 when in-person schools were closed in the U.S. RESULTS: Twenty-two percent of families incurred financial costs to support remote learning, and only 59% of school-based services received before COVID-19 continued during COVID-19 remote learning. Adolescents with ADHD had fewer routines and more remote learning difficulties than adolescents without ADHD. Parents of adolescents with ADHD had less confidence in managing remote learning and more difficulties in supporting home learning and home-school communication. Thirty-one percent of parents of adolescents with ADHD with an Individualized Education Program (IEP) or receiving academic accommodations (504 Plan) reported remote learning to be very challenging, compared with 18% of parents of adolescents with ADHD without an IEP/504 Plan, and only 4% of parents of adolescents with neither ADHD nor an IEP/504 Plan. Fewer adolescent routines, higher negative affect, and more difficulty concentrating because of COVID-19 were each associated with greater adolescent remote learning difficulties only in adolescents with ADHD. CONCLUSIONS: This study provides initial findings of the nature and impact of remote learning during the COVID-19 pandemic. It is imperative for schools and communities to provide the necessary supports to adolescents, particularly those with mental health and/or learning difficulties, and to their parents.

Phylogenetic analysis of SARS-CoV-2 in the Boston area highlights the role of recurrent importation and superspreading events.

SARS-CoV-2 has caused a severe, ongoing outbreak of COVID-19 in Massachusetts with 111,070 confirmed cases and 8,433 deaths as of August 1, 2020. To investigate the introduction, spread, and epidemiology of COVID-19 in the Boston area, we sequenced and analyzed 772 complete SARS-CoV-2 genomes from the region, including nearly all confirmed cases within the first week of the epidemic and hundreds of cases from major outbreaks at a conference, a nursing facility, and among homeless shelter guests and staff. The data reveal over 80 introductions into the Boston area, predominantly from elsewhere in the United States and Europe. We studied two superspreading events covered by the data, events that led to very different outcomes because of the timing and populations involved. One produced rapid spread in a vulnerable population but little onward transmission, while the other was a major contributor to sustained community transmission, including outbreaks in homeless populations, and was exported to several other domestic and international sites. The same two events differed significantly in the number of new mutations seen, raising the possibility that SARS-CoV-2 superspreading might encompass disparate transmission dynamics. Our results highlight the failure of measures to prevent importation into MA early in the outbreak, underscore the role of superspreading in amplifying an outbreak in a major urban area, and lay a foundation for contact tracing informed by genetic data.

Last night's sleep in relation to academic achievement and neurocognitive testing performance in adolescents with and without ADHD.

OBJECTIVES/BACKGROUND: Objectives were to (1) examine previous night's sleep in relation to next day performance on standardized academic achievement and neurocognitive assessments in adolescents, and (2) explore whether previous night's sleep is differentially associated with testing performance for adolescents with and without attention-deficit/hyperactivity disorder (ADHD). PARTICIPANTS/METHODS: Participants were 300 adolescents (ages 12-14 years; 55% male). Approximately half (53.6%) were diagnosed with ADHD. Adolescents provided ratings of their previous night's sleep quality, sleep duration, and number of night wakings and were administered standardized tests of processing speed and working memory, as well as word reading, numerical operations, and math fluency academic achievement. RESULTS: In analyses controlling for sex, race, medication use, time of testing, and ADHD group status, more night wakings the previous night were associated with significantly lower numerical operations and math fluency achievement scores and marginally lower working memory scores. Previous night's sleep was not associated with processing speed or reading achievement. ADHD status did not moderate sleep in relation to academic/neurocognitive performance. Participants reporting ≥2 night wakings the previous night had slightly over half a standard deviation lower scores on average compared to participants reporting 0 night wakings. CONCLUSIONS: This preliminary study suggests that previous night's wakings are associated with poorer mathematics performance the next day, regardless of ADHD status. This may be due to the detrimental effect of interrupted and fragmented sleep on attention and executive control. These findings have implications for clinicians and educators when considering contextual factors that may impact academic and neurocognitive testing performance.