Polygenic architecture of rare coding variation across 394,783 exomes.

Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes1-3. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear4. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes5. Rare coding variants (allele frequency < 1 × 10-3) explain 1.3% (s.e. = 0.03%) of phenotypic variance on average-much less than common variants-and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10-5). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder6,7 is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.

Partitioning gene-mediated disease heritability without eQTLs.

Unknown SNP-to-gene regulatory architecture complicates efforts to link noncoding GWAS associations with genes implicated by sequencing or functional studies. eQTLs are often used to link SNPs to genes, but expression in bulk tissue explains a small fraction of disease heritability. A simple but successful approach has been to link SNPs with nearby genes via base pair windows, but genes may often be regulated by SNPs outside their window. We propose the abstract mediation model (AMM) to estimate (1) the fraction of heritability mediated by the closest or kth-closest gene to each SNP and (2) the mediated heritability enrichment of a gene set (e.g., genes with rare-variant associations). AMM jointly estimates these quantities by matching the decay in SNP enrichment with distance from genes in the gene set. Across 47 complex traits and diseases, we estimate that the closest gene to each SNP mediates 27% (SE: 6%) of heritability and that a substantial fraction is mediated by genes outside the ten closest. Mendelian disease genes are strongly enriched for common-variant heritability; for example, just 21 dyslipidemia genes mediate 25% of LDL heritability (211× enrichment, p = 0.01). Among brain-related traits, genes involved in neurodevelopmental disorders are only about 4× enriched, but gene expression patterns are highly informative, as they have detectable differences in per-gene heritability even among weakly brain-expressed genes.

Delaying high school start times impacts depressed mood among students: evidence from a natural experiment.

PURPOSE: Delaying high school start times prolongs weekday sleep. However, it is not clear if longer sleep reduces depression symptoms and if the impact of such policy change is the same across groups of adolescents. METHODS: We examined how gains in weekday sleep impact depression symptoms in 2,134 high school students (mean age 15.16 ± 0.35 years) from the Minneapolis metropolitan area. Leveraging a natural experiment design, we used the policy change to delay school start times as an instrument to estimate the effect of a sustained gain in weekday sleep on repeatedly measured Kandel-Davies depression symptoms. We also evaluated whether allocating the policy change to subgroups with expected benefit could improve the impact of the policy. RESULTS: Over 2 years, a sustained half-hour gain in weekday sleep expected as a result of the policy change to delay start times decreased depression symptoms by 0.78 points, 95%CI (-1.32,-0.28), or 15.6% of a standard deviation. The benefit was driven by a decrease in fatigue and sleep-related symptoms. While symptoms of low mood, hopelessness, and worry were not affected by the policy on average, older students with greater daily screen use and higher BMI experienced greater improvements in mood symptoms than would be expected on average, signaling heterogeneity. Nevertheless, universal implementation outperformed prescriptive strategies. CONCLUSION: High school start time delays are likely to universally decrease fatigue and overall depression symptoms in adolescents. Students who benefit most with respect to mood are older, spend more time on screens and have higher BMI.

Genetic influence on cognitive development between childhood and adulthood.

Successful cognitive development between childhood and adulthood has important consequences for future mental and physical wellbeing, as well as occupational and financial success. Therefore, delineating the genetic influences underlying changes in cognitive abilities during this developmental period will provide important insights into the biological mechanisms that govern both typical and atypical maturation. Using data from the Philadelphia Neurodevelopmental Cohort (PNC), a large population-based sample of individuals aged 8 to 21 years old (n = 6634), we used an empirical relatedness matrix to establish the heritability of general and specific cognitive functions and determine if genetic factors influence cognitive maturation (i.e., Gene × Age interactions) between childhood and early adulthood. We found that neurocognitive measures across childhood and early adulthood were significantly heritable. Moreover, genetic variance on general cognitive ability, or g, increased significantly between childhood and early adulthood. Finally, we did not find evidence for decay in genetic correlation on neurocognition throughout childhood and adulthood, suggesting that the same genetic factors underlie cognition at different ages throughout this developmental period. Establishing significant Gene × Age interactions in neurocognitive functions across childhood and early adulthood is a necessary first step in identifying genes that influence cognitive development, rather than genes that influence cognition per se. Moreover, since aberrant cognitive development confers risk for several psychiatric disorders, further examination of these Gene × Age interactions may provide important insights into their etiology.

A scoping review on the methods of assessment and role of resilience on function and movement-evoked pain when experiencing a musculoskeletal injury.

BACKGROUND: Resilience refers to an individual's ability to maintain effective functioning, by resisting, withstanding or recovering from stressors or adversity, including pain associated with physical injury (J Clin Psychol Med Settings 28:518-28, 2021). The aim of this scoping review is to determine the role of resilience in the experience of movement-evoked pain (MEP) and return to functional activity following a musculoskeletal injury. METHODS: This review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews and the scoping review protocol of the Joanna Briggs Institute (JBI). Five databases and one grey literature database were searched using predetermined key words and index terms to capture published and unpublished records on the topic. Two authors independently screened the title and abstract of each record, with the full-text of eligible records being reviewed. Papers were eligible for inclusion if they examined the population, concept and context of interest, were written in English and the full text was available. Data were extracted from each eligible record to guide discussion of the available literature on this topic. RESULTS: Of 4771 records, 2695 articles underwent screening based on their title and abstract. After title and abstract screening 132 articles were eligible for full text review, with 24 articles included in the final analysis. This review identified that psychological resilience has primarily been investigated in the context of a range of age-related pathologies. The choice of functional and movement-evoked pain assessments in the included studies were often guided by the pathology of interest, with some being general or injury specific. CONCLUSION: This scoping review identified inconsistent conclusions regarding the role of resilience in the experience of MEP and the ability to return to function for older adults with a musculoskeletal injury. This scoping review highlights the need for longitudinal research to be conducted that allows a broader age range, including younger adults, to determine if multidimensional resilience may promote recovery form musculoskeletal injury.

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions--phenotypically and genetically--although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

Examining and interpreting the female protective effect against autistic behavior.

Male preponderance in autistic behavioral impairment has been explained in terms of a hypothetical protective effect of female sex, yet little research has tested this hypothesis empirically. If females are protected, they should require greater etiologic load to manifest the same degree of impairment as males. The objective of this analysis was to examine whether greater familial etiologic load was associated with quantitative autistic impairments in females compared with males. Subjects included 3,842 dizygotic twin pairs from the Twins Early Development Study (TEDS) and 6,040 dizygotic twin pairs from the Child and Adolescent Twin Study of Sweden (CATSS). In both samples, we compared sibling autistic traits between female and male probands, who were identified as children scoring in the top 90th and 95th percentiles of the population autistic trait distributions. In both TEDS and CATSS, siblings of female probands above the 90th percentile had significantly more autistic impairments than the siblings of male probands above the 90th percentile. The siblings of female probands above the 90th percentile also had greater categorical recurrence risk in both TEDS and CATSS. Results were similar in probands above the 95th percentile. This finding, replicated across two nationally-representative samples, suggests that female sex protects girls from autistic impairments and that girls may require greater familial etiologic load to manifest the phenotype. It provides empirical support for the hypothesis of a female protective effect against autistic behavior and can be used to inform and interpret future gene finding efforts in autism spectrum disorders.

Genetic research in autism spectrum disorders.

PURPOSE OF REVIEW: The recent explosion of genetic findings in autism spectrum disorder (ASD) research has improved knowledge of the disorder's underlying biology and etiologic architecture. This review introduces concepts and results from recent genetic studies and discusses the manner in which those findings can influence the trajectory of ASD research. RECENT FINDINGS: Large consortium studies have associated ASDs with many types of genetic risk factors, including common polygenic risk, de novo single nucleotide variants, copy number variants, and rare inherited variants. In aggregate, these results confirm the heterogeneity and complexity of ASDs. The rare variant findings in particular point to genes and pathways that begin to bridge the gap between behavior and biology. SUMMARY: Genetic studies have the potential to identify the biological underpinnings of ASDs and other neuropsychiatric disorders. The data they generate are already being used to examine disease pathways and pathogenesis. The results also speak to ASD heterogeneity and, in the future, may be used to stratify research studies and treatment trials.

Bipolar polygenic loading and bipolar spectrum features in major depressive disorder.

OBJECTIVES: Family and genetic studies indicate overlapping liability for major depressive disorder and bipolar disorder. The purpose of the present study was to determine whether this shared genetic liability influences clinical presentation. METHODS: A polygenic risk score for bipolar disorder, derived from a large genome-wide association meta-analysis, was generated for each subject of European-American ancestry (n = 1,274) in the Sequential Treatment Alternatives to Relieve Depression study (STAR*D) outpatient major depressive disorder cohort. A hypothesis-driven approach was used to test for association between bipolar disorder risk score and features of depression associated with bipolar disorder in the literature. Follow-up analyses were performed in two additional cohorts. RESULTS: A generalized linear mixed model including seven features hypothesized to be associated with bipolar spectrum illness was significantly associated with bipolar polygenic risk score [F = 2.07, degrees of freedom (df) = 7, p = 0.04]. Features included early onset, suicide attempt, recurrent depression, atypical depression, subclinical mania, subclinical psychosis, and severity. Post-hoc univariate analyses demonstrated that the major contributors to this omnibus association were onset of illness at age ≤ 18 years [odds ratio (OR) = 1.2, p = 0.003], history of suicide attempt (OR = 1.21, p = 0.03), and presence of at least one manic symptom (OR = 1.16, p = 0.02). The maximal variance in these traits explained by polygenic score ranged from 0.8% to 1.1%. However, analyses in two replication cohorts testing a five-feature model did not support this association. CONCLUSIONS: Bipolar genetic loading appeared to be associated with bipolar-like presentation in major depressive disorder in the primary analysis. However, the results were at most inconclusive because of lack of replication. Replication efforts were challenged by different ascertainment and assessment strategies in the different cohorts. The methodological approach described here may prove useful in applying genetic data to clarify psychiatric nosology in future studies.

Language and traits of autism spectrum conditions: evidence of limited phenotypic and etiological overlap.

Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by ~3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation = -0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation = 0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier.

Parental Perspectives Regarding the Return of Genomic Research Results in Neurodevelopmental Disorders in South Africa: Anticipated Impact and Preferences.

Few policies and little research exist regarding the disclosure of genomic results to research participants in Africa. As understanding participant preferences would be pivotal to the success of the feedback process, this study set out to address this issue by engaging with enrolled participants from an ongoing genomics research project on neurodevelopmental disorders with the aim to assess the anticipated impact of receiving pertinent results and explore the preferences for feedback in a South-African context. Twelve semi-structured interviews were conducted with 17 parents of children participating in the research study. Transcribed interview data and observational notes were analysed using thematic analysis and framework matrices. Participants linked their own meaning to the impact of receiving a pertinent result and perceived the information as useful for reasons other than only clinical utility. These included closure, improved management of their child's condition and information regarding recurrence risks. In terms of preferences for feedback, an in-person result delivery session, conducted by a member of the study team or medical professional familiar with their child was preferred. In addition, participants felt a sense of ownership over their blood or their contribution to the research study, finding meaning even in non-pertinent (secondary findings) or negative results. These findings provide insight into the type of discussions that may be valuable in enabling the development of best practices and guidelines for the return of individual genetic research results, in a culturally appropriate manner, within South-African communities.

Phenotypic and ancestry-related assortative mating in autism.

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). LIMITATIONS: 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.

Genetic predictors of risk and resilience in psychiatric disorders: a cross-disorder genome-wide association study of functional impairment in major depressive disorder, bipolar disorder, and schizophrenia.

Functional impairment is one of the most enduring, intractable consequences of psychiatric disorders and is both familial and heritable. Previous studies have suggested that variation in functional impairment can be independent of symptom severity. Here we report the first genome-wide association study (GWAS) of functional impairment in the context of major mental illness. Participants of European-American descent (N = 2,246) were included from three large treatment studies of bipolar disorder (STEP-BD) (N = 765), major depressive disorder (STAR*D) (N = 1091), and schizophrenia (CATIE) (N = 390). At study entry, participants completed the SF-12, a widely used measure of health-related quality of life. We performed a GWAS and pathway analysis of the mental and physical components of health-related quality of life across diagnosis (∼1.6 million single nucleotide polymorphisms), adjusting for psychiatric symptom severity. Psychiatric symptom severity was a significant predictor of functional impairment, but it accounted for less than one-third of the variance across disorders. After controlling for diagnostic category and symptom severity, the strongest evidence of genetic association was between variants in ADAMTS16 and physical functioning (P = 5.87 × 10(-8) ). Pathway analysis did not indicate significant enrichment after correction for gene clustering and multiple testing. This study illustrates a phenotypic framework for examining genetic contributions to functional impairment across psychiatric disorders.

Validity of the SNAP-IV For ADHD Assessment in South African Children With Neurodevelopmental Disorders.

This study investigated the psychometric properties of the Swanson, Nolan, and Pelham ADHD Rating Scale (SNAP-IV) in a sample of South African children with neurodevelopmental disorders (n = 201), primarily Autism Spectrum Disorder and Intellectual Disability. We conducted a confirmatory factor analysis to inspect the two-factor structure of the SNAP-IV. We also calculated ordinal coefficient alpha to estimate internal consistency. Fit statistics for the two-factor model approached acceptable levels. The model fit improved slightly after removing an item related to spoken language. The subscales had acceptable internal consistencies. Findings partially support the use of the SNAP-IV in this group of children. However, there are limitations to its performance in this population likely related to the presence of neurodevelopmental disorders.

Phenotype and genetic analysis of data collected within the first year of NeuroDev.

Genetic association studies have made significant contributions to our understanding of the etiology of neurodevelopmental disorders (NDDs). However, these studies rarely focused on the African continent. The NeuroDev Project aims to address this diversity gap through detailed phenotypic and genetic characterization of children with NDDs from Kenya and South Africa. We present results from NeuroDev's first year of data collection, including phenotype data from 206 cases and clinical genetic analyses of 99 parent-child trios. Most cases met criteria for global developmental delay/intellectual disability (GDD/ID, 80.3%). Approximately half of the children with GDD/ID also met criteria for autism. Analysis of exome-sequencing data identified a pathogenic or likely pathogenic variant in 13 (17%) of the 75 cases from South Africa and 9 (38%) of the 24 cases from Kenya. Data from the trio pilot are publicly available, and the NeuroDev Project will continue to develop resources for the global genetics community.

A multivariate twin study of autistic traits in 12-year-olds: testing the fractionable autism triad hypothesis.

Autistic traits-social impairment, communication impairment, and restricted and repetitive behaviors and interests-are heritable in the general population. Previous analyses have consistently reported limited genetic and environmental overlap between autistic trait domains in samples assessed in middle childhood. Here we extend this research to parent-report data for 12-year-olds. Data from 5,944 pairs in the Twins Early Development Study were analyzed to explore the domain-specific heritability and degree of shared genetic and environmental influences across different autistic traits in the general population and among individuals scoring in the top 5% of each domain. Sex differences in the etiological estimates were also tested in these analyses. Autistic traits were moderately to highly heritable (0.58-0.88) at age 12. Bivariate genetic correlations in the full sample (0.18-0.40) and the extremes (0.24-0.67), as well as even lower unique environmental correlations, all suggested considerable fractionation of genetic and environmental influences across autistic trait domains, in line with previous findings.

Bringing a developmental perspective to anxiety genetics.

Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review the psychiatric and genetic epidemiological evidence that supports such a framework, including the early onset and chronic course of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders.

Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis.

Importance: Presence of developmental delays in autism is well established, yet few studies have characterized variability in developmental milestone attainment in this population. Objective: To characterize variability in the age at which autistic individuals attain key developmental milestones based on co-occurring intellectual disability (ID), presence of a rare disruptive genetic variant associated with neurodevelopmental disorders (NDD), age at autism diagnosis, and research cohort membership. Design: The study team harmonized data from 4 cross-sectional autism cohorts: the Autism Genetics Research Exchange (n = 3284; 1997-2015), The Autism Simplex Collection (n = 694; 2008-2011), the Simons Simplex Collection (n = 2753; 2008-2011), and the Simons Foundation Powering Autism Research for Knowledge (n = 10 367; 2016-present). The last sample further included 4145 siblings without an autism diagnosis or ID. Participants: Convenience sample of 21 243 autistic individuals or their siblings without an autism diagnosis aged 4 to 17 years. Main Outcomes and Measures: Parents reported ages at which participants attained key milestones including smiling, sitting upright, crawling, walking, spoon-feeding self, speaking words, speaking phrases, and acquiring bladder and bowel control. A total of 5295 autistic individuals, and their biological parents, were genetically characterized to identify de novo variants in NDD-associated genes. The study team conducted time-to-event analyses to estimate and compare percentiles in time with milestone attainment across autistic individuals, subgroups of autistic individuals, and the sibling sample. Results: Seventeen thousand ninety-eight autistic individuals (mean age, 9.15 years; 80.8% male) compared with 4145 siblings without autism or ID (mean age, 10.2 years; 50.2% female) showed delays in milestone attainment, with median (IQR) delays ranging from 0.7 (0.3-1.6) to 19.7 (11.4-32.2) months. More severe and more variable delays in autism were associated with the presence of co-occurring ID, carrying an NDD-associated rare genetic variant, and being diagnosed with autism by age 5 years. More severe and more variable delays were also associated with membership in earlier study cohorts, consistent with autism's diagnostic and ascertainment expansion over the last 30 years. Conclusions and Relevance: As the largest summary to date of developmental milestone attainment in autism, to our knowledge, this study demonstrates substantial developmental variability across different conditions and provides important context for understanding the phenotypic and etiological heterogeneity of autism.

Genetic correlates of phenotypic heterogeneity in autism.

The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.

In vivo visualization and molecular targeting of the cardiac conduction system.

Accidental injury to the cardiac conduction system (CCS), a network of specialized cells embedded within the heart and indistinguishable from the surrounding heart muscle tissue, is a major complication in cardiac surgeries. Here, we addressed this unmet need by engineering targeted antibody-dye conjugates directed against the CCS, allowing for the visualization of the CCS in vivo following a single intravenous injection in mice. These optical imaging tools showed high sensitivity, specificity, and resolution, with no adverse effects on CCS function. Further, with the goal of creating a viable prototype for human use, we generated a fully human monoclonal Fab that similarly targets the CCS with high specificity. We demonstrate that, when conjugated to an alternative cargo, this Fab can also be used to modulate CCS biology in vivo, providing a proof of principle for targeted cardiac therapeutics. Finally, in performing differential gene expression analyses of the entire murine CCS at single-cell resolution, we uncovered and validated a suite of additional cell surface markers that can be used to molecularly target the distinct subcomponents of the CCS, each prone to distinct life-threatening arrhythmias. These findings lay the foundation for translational approaches targeting the CCS for visualization and therapy in cardiothoracic surgery, cardiac imaging, and arrhythmia management.