Longitudinal studies of bipolar patients and their families: translating findings to advance individualized risk prediction, treatment and research.

BACKGROUND: Bipolar disorder is a broad diagnostic construct associated with significant phenotypic and genetic heterogeneity challenging progress in clinical practice and discovery research. Prospective studies of well-characterized patients and their family members have identified lithium responsive (LiR) and lithium non-responsive (LiNR) subtypes that hold promise for advancement. METHOD: In this narrative review, relevant observations from published longitudinal studies of well-characterized bipolar patients and their families spanning six decades are highlighted. DSM diagnoses based on SADS-L interviews were decided in blind consensus reviews by expert clinicians. Genetic, neurobiological, and psychosocial factors were investigated in subsets of well-characterized probands and adult relatives. Systematic maintenance trials of lithium, antipsychotics, and lamotrigine were carried out. Clinical profiles that included detailed histories of the clinical course, symptom sets and disorders segregating in families were documented. Offspring of LiR and LiNR families were repeatedly assessed up to 20 years using KSADS-PL format interviews and DSM diagnoses and sub-threshold symptoms were decided by expert clinicians in blind consensus reviews using all available clinical and research data. RESULTS: A characteristic clinical profile differentiated bipolar patients who responded to lithium stabilization from those who did not. The LiR subtype was characterized by a recurrent fully remitting course predominated by depressive episodes and a positive family history of episodic remitting mood disorders, and not schizophrenia. Response to lithium clustered in families and the characteristic clinical profile predicted lithium response, with the episodic remitting course being a strong correlate. There is accumulating evidence that genetic and neurobiological markers differ between LiR and LiNR subtypes. Further, offspring of bipolar parents subdivided by lithium response differed in developmental history, clinical antecedents and early course of mood disorders. Moreover, the nature of the emergent course bred true from parent to offspring, independent of the nature of emergent psychopathology. CONCLUSIONS: Bipolar disorders are heterogeneous and response to long-term lithium is associated with a familial subtype with characteristic course, treatment response, family history and likely pathogenesis. Incorporating distinctive clinical profiles that index valid bipolar subtypes into routine practice and research will improve patient outcomes and advance the development and translation of novel treatment targets to improve prevention and early intervention.

Homozygous HLA-DQB1*06:02 combined with T-cell receptor alpha polymorphism results in narcolepsy onset - A familial case report.

Narcolepsy is a life-long neurological disorder with well-established genetic risk factors. Human leukocyte antigen-DQB1*06:02 remains the strongest genetic predeterminant; however, polymorphisms in genes encoding the T-cell receptor alpha chain are also strongly linked. This case report shows the inheritance pathway of these genetic markers contributing to narcolepsy onset in a 17-year-old female.

Assessing the use of GEE methods for analyzing binary outcomes in family studies: the Strong Heart Family Study.

The generalized estimating equations method (GEE) is commonly applied to analyze data obtained from family studies. GEE is well known for its robustness on misspecification of correlation structure. However, the unbalanced distribution of family sizes and complicated genetic relatedness structure within each family may challenge GEE performance. We focused our research on binary outcomes. To evaluate the performance of GEE, we conducted a series of simulations, on data generated adopting the kinship matrix (correlation structure within each family) from the Strong Heart Family Study (SHFS). We performed a fivefold cross-validation to further evaluate the GEE predictive power on data from the SHFS. A Bayesian modeling approach, with direct integration of the kinship matrix, was also included to contrast with GEE. Our simulation studies revealed that GEE performs well on a binary outcome from families having a relatively simple kinship structure. However, data with a binary outcome generated from families with complex kinship structures, especially with a large genetic variance, can challenge the performance of GEE.

Genome sequencing of Pakistani families with male infertility identifies deleterious genotypes in SPAG6, CCDC9, TKTL1, TUBA3C, and M1AP.

BACKGROUND: There are likely to be hundreds of monogenic forms of human male infertility. Whole genome sequencing (WGS) is the most efficient way to make progress in mapping the causative genetic variants, and ultimately improve clinical management of the disease in each patient. Recruitment of consanguineous families is an effective approach to ascertain the genetic forms of many diseases. OBJECTIVES: To apply WGS to large consanguineous families with likely hereditary male infertility and identify potential genetic cases. MATERIALS AND METHODS: We recruited seven large families with clinically diagnosed male infertility from rural Pakistan, including five with a history of consanguinity. We generated WGS data on 26 individuals (3-5 per family) and analyzed the resulting data with a computational pipeline to identify potentially causal single nucleotide variants, indels, and copy number variants. RESULTS: We identified plausible genetic causes in five of the seven families, including a homozygous 10 kb deletion of exon 2 in a well-established male infertility gene (M1AP), and biallelic missense substitutions (SPAG6, CCDC9, TUBA3C) and an in-frame hemizygous deletion (TKTL1) in genes with emerging relevance. DISCUSSION AND CONCLUSION: The rate of genetic findings using the current approach (71%) was much higher than what we recently achieved using whole-exome sequencing (WES) of unrelated singleton cases (20%). Furthermore, we identified a pathogenic single-exon deletion in M1AP that would be undetectable by WES. Screening more families with WGS, especially in underrepresented populations, will further reveal the types of variants underlying male infertility and accelerate the use of genetics in the patient management.

A Meta-analysis of the Relations Between Socioeconomic Status and Parenting Practices.

The question of why parents parent the way they do is central in parenting studies. Research about the predictors of parenting has been guided by Belsky's classical model of parenting determinants. In this model, socioeconomic status was not explicitly considered as a determinant of parenting. However, there is ample research that came later that found relations between socioeconomic status and parenting. The aim of this study was to find an aggregate estimate of the relations between socioeconomic status and parenting practices using meta-analytic methods. We found that socioeconomic status was positively linked to positive parenting, and negatively linked to negative parenting. In particular, socioeconomic status was positively linked to parental warmth and parental behavioral control, but negatively linked to parental psychological control. The relations between socioeconomic status and positive or negative parenting were not moderated by child's age or sex and did not differ based on the type of socioeconomic status indicator. Moreover, all the correlations were small in magnitude, and were comparable to other predictors of parenting such as parent's depression, parent's personality traits, and child's temperament. Our results suggest that parent's overall socioeconomic status, or its different constituents, supplement Belsky's model of parenting determinants.

Whole-Exome Sequencing in a Family with an Unexplained Tendency for Venous Thromboembolism: Multicomponent Prediction of Low-Frequency Variant Deleteriousness and of Individual Protein Interaction.

Whole-exome sequencing (WES) in families with an unexplained tendency for venous thromboembolism (VTE) may favor detection of low-frequency variants in genes with known contribution to hemostasis or associated with VTE-related phenotypes. WES analysis in six family members, three of whom affected by documented VTE, filtered for MAF < 0.04 in 192 candidate genes, revealed 22 heterozygous (16 missense and six synonymous) variants in patients. Functional prediction by multi-component bioinformatics tools, implemented by a database/literature search, including ClinVar annotation and QTL analysis, prioritized 12 missense variants, three of which (CRP Leu61Pro, F2 Asn514Lys and NQO1 Arg139Trp) were present in all patients, and the frequent functional variants FGB Arg478Lys and IL1A Ala114Ser. Combinations of prioritized variants in each patient were used to infer functional protein interactions. Different interaction patterns, supported by high-quality evidence, included eight proteins intertwined in the "acute phase" (CRP, F2, SERPINA1 and IL1A) and/or in the "fibrinogen complex" (CRP, F2, PLAT, THBS1, VWF and FGB) significantly enriched terms. In a wide group of candidate genes, this approach highlighted six low-frequency variants (CRP Leu61Pro, F2 Asn514Lys, SERPINA1 Arg63Cys, THBS1 Asp901Glu, VWF Arg1399His and PLAT Arg164Trp), five of which were top ranked for predicted deleteriousness, which in different combinations may contribute to disease susceptibility in members of this family.

Improving parents' ability to advocate for services for youth with autism: A randomized clinical trial.

Youth with autism face challenges accessing services as they transition to adulthood. Improving parents' ability to advocate for services on behalf of their youth may be an effective way to improve service access and ultimately transition outcomes in this group. In this study, we tested whether participating in an advocacy intervention improved parents' ability to advocate for services for their transition-aged youth with autism. One hundred and eighty-five parents of youth with autism ages 16-26, recruited across three states in the U.S., were randomized to one of two experimental conditions. The treatment condition received the ASSIST program, a 12-week (24-h) group-based intervention. The control condition received the same written materials as the treatment condition. Primary outcomes for this report-parent advocacy ability-were collected at baseline (prior to randomization) and post-test (immediately after the treatment group finished the 12-week program) by survey. After taking ASSIST, the treatment condition had greater gains than controls in knowledge of adult services (B = -1.62, CI = -2.33 to -0.90) and perceived advocacy skills (B = -0.19, CI = -0.33 to -0.04). Participants who had less knowledge, lower perceived advocacy skills, and less active coping styles at baseline had the greatest treatment gains. Findings suggest that ASSIST is effective in improving parent advocacy ability and may be most beneficial for parents who experience greater challenges advocating for their son/daughter with autism. Future research will examine whether gains in parent advocacy ability leads to improvements in service access and post-school outcomes for transition-age youth with autism.

Associations among Financial Well-Being, Daily Relationship Tension, and Daily Affect in Two Adult Cohorts Separated by the Great Recession.

Financial well-being may be an important context for daily emotional reactivity to relationship tension (e.g., arguments) whose salience varies across historical time or as a function of exposure to economic downturns. This study investigated how emotional reactivity, operationalized as daily fluctuations in negative and positive affect associated with the occurrence of daily relationship tension, varied by financial well-being among those who were and were not exposed to the Great Recession of 2008. Two matched, independent subsamples of partnered individuals from the National Study of Daily Experiences completed identical 8-day diary protocols, one before the Great Recession (n = 587) and one after (n = 351). Individuals reported higher negative affect and lower positive affect on days when relationship tension occurred. Further, results indicated that negative affect reactivity, but not positive affect reactivity, was moderated by both financial well-being and cohort status. For the pre-recession cohort, negative affect reactivity was stronger among those with lower financial well-being. However, among the post-recession cohort, financial well-being did not moderate negative affect reactivity to relationship tension. Findings highlight the utility of considering major societal events, such as economic downturns, to understand variability in emotional reactivity to day-to-day relationship tension in the context of financial well-being, as the salience of financial well-being in the ways relationship tension and negative affect are related on a daily basis appears to vary by historical context.

Why we need families in genomic research on developmental psychopathology.

Background: Fundamental questions about the roles of genes, environments, and their interplay in developmental psychopathology have traditionally been the domain of twin and family studies. More recently, the rapidly growing availability of large genomic datasets, composed of unrelated individuals, has generated novel insights. However, there are major stumbling blocks. Only a small fraction of the total genetic influence on childhood psychopathology estimated from family data is captured with measured DNA. Moreover, genetic influence identified using DNA is often confounded with indirect genetic effects of relatives, population stratification and assortative mating. Methods: The goal of this paper is to review how combining DNA-based genomic research with family-based quantitative genetics helps to address key issues in genomics and push knowledge further. Results: We focus on three approaches to obtaining more accurate and novel genomic findings on the developmental aetiology of psychopathology: (a) using knowledge from twin and family studies, (b) triangulating with twin and family studies, and (c) integrating data and methods with twin and family studies. Conclusion: We support the movement towards family-based genomic research, and show that developmental psychologists are particularly well-placed to contribute hypotheses, analysis tools, and data.

Parental health in the context of public family care proceedings: A scoping review of evidence and interventions.

BACKGROUND: Child protective services (CPS), or their equivalent, have statutory power to remove children from birth parents in instances of child abuse, neglect, or concerns around parenting capacity via public family care proceedings. Parents who have children subject to proceedings, 'birth parents', often have complex health and social care needs. OBJECTIVE: We aimed to review what is known about the health needs of birth parents and the interventions implemented to support these health needs. METHODS: We searched PubMed, Scopus, and grey literature using a systematic strategy of key concepts "health", "care proceedings", and "parents". We included all publications in English that reported parental health in the context of care proceedings from the 1st of January 2000 to the 1st of March 2021. RESULTS: Included studies (n = 61) reported on maternal health (57 %) or the health of both parents (40 %), with only one study reporting on fathers alone. We conceptually categorised parental health need (n = 41) into i) mental health, ii) physical health, iii) substance misuse, iv) developmental disorders, and v) reproductive health. Health inequities and poor access to services were described across all categories, with longstanding issues often pre-dating proceedings or the child's birth. All interventions supporting parental health (n = 20) were targeted at mothers, with some supporting fathers (n = 8), formally or informally. We grouped similar interventions into three types: alternative family courts, wrap-around services, and specialist advocacy/peer support. CONCLUSIONS: Parents who have children subject to care proceedings have complex health needs that pre-date CPS concerns. The studies included in our review strongly suggest that health issues are exacerbated by child removal, triggering deteriorations in mental health, poor antenatal health for subsequent pregnancies, and avoidable mortality. Findings highlight the need for targeted and timely intervention for parents to improve whole-family outcomes. There are models that have been designed, implemented, and tested using relationship-based, trauma-informed, multidisciplinary, family-focused, and long-term approaches.

Error-Related Brain Activity in Patients With Obsessive-Compulsive Disorder and Unaffected First-Degree Relatives: Evidence for Protective Patterns.

Background: Indicators of increased error monitoring are associated with obsessive-compulsive disorder (OCD), as shown in electroencephalography and functional magnetic resonance imaging studies. As most studies used strictly controlled samples (excluding comorbidity and medication), it remains open whether these findings extend to naturalistic settings. Thus, we assessed error-related brain activity in a large, naturalistic OCD sample. We also explored which activity patterns might qualify as vulnerability endophenotypes or protective factors for the disorder. To this aim, a sample of unaffected first-degree relatives of patients with OCD was also included. Methods: Participants (84 patients with OCD, 99 healthy control participants, and 37 unaffected first-degree relatives of patients with OCD) completed a flanker task while blood oxygen level-dependent responses were measured with functional magnetic resonance imaging. Aberrant error-related brain activity in patients and relatives was identified. Results: Patients with OCD showed increased error-related activity in the supplementary motor area and within the default mode network, specifically in the precuneus and postcentral gyrus. Unaffected first-degree relatives showed increased error-related activity in the bilateral inferior frontal gyrus. Conclusions: Increased supplementary motor area and default mode network activity in patients with OCD replicates previous studies and might indicate excessive error signals and increased self-referential error processing. Increased activity of the inferior frontal gyrus in relatives may reflect increased inhibition. Impaired response inhibition in OCD has been demonstrated in several studies and might contribute to impairments in suppressing compulsive actions. Thus, increased inferior frontal gyrus activity in the unaffected relatives of patients with OCD may have contributed to protection from symptom development.

Datasets for a simulated family-based exome-sequencing study.

We present simulated exome-sequencing data for 150 families from a North American admixed population, ascertained to contain at least four members affected with lymphoid cancer. These data include information on the ascertained families as well as single-nucleotide variants on the exome of affected family members. We provide a brief overview of the simulation steps and links to the associated software scripts. The resulting data are useful to identify genomic patterns and disease inheritance in families with multiple disease-affected members.

The roles of familial transmission and smoking during pregnancy on executive function skills: A sibling-comparison study.

This research examines maternal smoking during pregnancy and risk for poorer executive function in siblings discordant for exposure. Data (N = 173 families) were drawn from the Missouri Mothers and Their Children study, a sample, identified using birth records (years 1998-2005), in which mothers changed smoking behavior between two pregnancies (Child 1 [older sibling]: M age = 12.99; Child 2 [younger sibling]: M age = 10.19). A sibling comparison approach was used, providing a robust test for the association between maternal smoking during pregnancy and different aspects of executive function in early-mid adolescence. Results suggested within-family (i.e., potentially causal) associations between maternal smoking during pregnancy and one working memory task (visual working memory) and one response inhibition task (color-word interference), with increased exposure associated with decreased performance. Maternal smoking during pregnancy was not associated with stop-signal reaction time, cognitive flexibility/set-shifting, or auditory working memory. Initial within-family associations between maternal smoking during pregnancy and visual working memory as well as color-word interference were fully attenuated in a model including child and familial covariates. These findings indicate that exposure to maternal smoking during pregnancy may be associated with poorer performance on some, but not all skills assessed; however, familial transmission of risk for low executive function appears more important.

Pre-Clinical Autoimmunity in Lupus Relatives: Self-Reported Questionnaires and Immune Dysregulation Distinguish Relatives Who Develop Incomplete or Classified Lupus From Clinically Unaffected Relatives and Unaffected, Unrelated Individuals.

Systemic lupus erythematosus (SLE) is propelled by pathogenic autoantibody (AutoAb) and immune pathway dysregulation. Identifying populations at risk of reaching classified SLE is essential to curtail inflammatory damage. Lupus blood relatives (Rel) have an increased risk of developing SLE. We tested factors to identify Rel at risk of developing incomplete lupus (ILE) or classified SLE vs. clinically unaffected Rel and healthy controls (HC), drawing from two unique, well characterized lupus cohorts, the lupus autoimmunity in relatives (LAUREL) follow-up cohort, consisting of Rel meeting <4 ACR criteria at baseline, and the Lupus Family Registry and Repository (LFRR), made up of SLE patients, lupus Rel, and HC. Medical record review determined ACR SLE classification criteria; study participants completed the SLE portion of the connective tissue disease questionnaire (SLE-CSQ), type 2 symptom questions, and provided samples for assessment of serum SLE-associated AutoAb specificities and 52 plasma immune mediators. Elevated SLE-CSQ scores were associated with type 2 symptoms, ACR scores, and serology in both cohorts. Fatigue at BL was associated with transition to classified SLE in the LAUREL cohort (p≤0.01). Increased levels of BLyS and decreased levels of IL-10 were associated with type 2 symptoms (p<0.05). SLE-CSQ scores, ACR scores, and accumulated AutoAb specificities correlated with levels of multiple inflammatory immune mediators (p<0.05), including BLyS, IL-2Rα, stem cell factor (SCF), soluble TNF receptors, and Th-1 type mediators and chemokines. Transition to SLE was associated with increased levels of SCF (p<0.05). ILE Rel also had increased levels of TNF-α and IFN-γ, offset by increased levels of regulatory IL-10 and TGF-ß (p<0.05). Clinically unaffected Rel (vs. HC) had higher SLE-CSQ scores (p<0.001), increased serology (p<0.05), and increased inflammatory mediator levels, offset by increased IL-10 and TGF-ß (p<0.01). These findings suggest that Rel at highest risk of transitioning to classified SLE have increased inflammation coupled with decreased regulatory mediators. In contrast, clinically unaffected Rel and Rel with ILE demonstrate increased inflammation offset with increased immune regulation, intimating a window of opportunity for early intervention and enrollment in prevention trials.

A Novel Homozygous Frameshift Mutation in ITGB3 Causes Glanzmann's Thrombasthenia.

The objective of this study was to elucidate the molecular characteristics of a Chinese family with Glanzmann's thrombasthenia (GT). The proband was diagnosed with GT based on clinical manifestations, platelet aggregation, and the expression of CD41 and CD61 in platelets. Whole-exome and Sanger sequencing were used to detect genetic defects related to GT in the proband and the family of the pedigree. Whole-exome sequencing showed a c.1784-1802delinsGTCACA, p. S595Cfs*70 homozygous mutation in exon 11 of the ITGB3 gene in the proband. Heterozygous mutations were found in the proband's parents, grandmother, uncle, aunt, and younger brother. This novel p. S595Cfs*70 ITGB3 gene mutation is not present in the 1000 Genomes and ExAC databases.

Parenting-allocated time in families of the Ural Russian region: amounts and determinants / Tempo alocado para a paternidade em famílias da região Ural da Rússia: quantidades e determinantes / Tiempo asignado a la crianza en familias de la región Ural de Rusia: cantidades y determinantes

Abstract This study aims to measure the time allocated to child raising using parents' self-assessment and the criterion of subjective time sufficiency or insufficiency. We surveyed 545 Russian parents from the Ural region and used factor analysis to identify the main determinants that affect the self-assessment of time allocated to parenting. We found that parents in the Russian Ural region believe they do not spend enough time with their children. Reasons for the insufficient amount of time allocated to parenting are the following: overload of labor duties at home and at work, psychological causes of intergenerational interaction, external reasons − studies, poor health, the need to care for other relatives and so on.

Resumo Este estudo tenta medir o tempo alocado aos filhos por meio da autoavaliação dos pais e do critério de suficiência subjetiva ou tempo insuficiente. Foram pesquisados 545 pais russos da região dos Urais e utilizou-se a análise fatorial para identificar os principais determinantes que afetam a autoavaliação do tempo alocado pelos pais. Verificou-se que os pais nas regiões russas dos Urais têm uma opinião comum de que não passam tempo suficiente com seus filhos. As razões para o tempo insuficiente alocado à educação dos filhos são as seguintes: sobrecarga de tarefas em casa e no trabalho; causas psicológicas de interação intergeracional; e razões externas, como estudo, saúde precária e necessidade de cuidar de outros parentes.

Resumen Este estudio intenta medir el tiempo asignado a los niños por medio de la autoevaluación de los padres y del criterio de suficiencia subjetiva o de insuficiencia de tiempo. Se encuestaron 545 padres rusos de la región de los Urales y se usó el análisis factorial para identificar los principales determinantes que afectan la autoevaluación del tiempo asignado a la crianza de los hijos. Descubrimos que en las regiones rusas los padres tienen la opinión común de que no pasan suficiente tiempo con sus hijos. Las razones para la cantidad insuficiente de tiempo asignado a la crianza de los hijos son la sobrecarga de deberes laborales en el hogar y en el trabajo, causas psicológicas de la interacción intergeneracional, o razones externas como estudio, mala salud o necesidad de cuidar a otros familiares.

Towards Understanding the Genetic Nature of Vasovagal Syncope.

Syncope, defined as a transient loss of consciousness caused by transient global cerebral hypoperfusion, affects 30-40% of humans during their lifetime. Vasovagal syncope (VVS) is the most common cause of syncope, the etiology of which is still unclear. This review summarizes data on the genetics of VVS, describing the inheritance pattern of the disorder, candidate gene association studies and genome-wide studies. According to this evidence, VVS is a complex disorder, which can be caused by the interplay between genetic factors, whose contribution varies from monogenic Mendelian inheritance to polygenic inherited predisposition, and external factors affecting the monogenic (resulting in incomplete penetrance) and polygenic syncope types.

Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk.

BACKGROUND: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling. METHODS: We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation. RESULTS: All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power-with the exception of isolated rare inherited pathogenic variants -does not yet reach a threshold that would typically be considered actionable for reproductive decision-making. CONCLUSIONS: Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study.

Heritability of quantitative autism spectrum traits in adults: A family-based study.

Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h2  = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD.

Twin studies to GWAS: there and back again.

The field of human behavioral genetics has come full circle. It began by using twin/family studies to estimate the relative importance of genetic and environmental influences. As large-scale genotyping became cost-effective, genome-wide association studies (GWASs) yielded insights about the nature of genetic influences and new methods that use GWAS data to estimate heritability and genetic correlations invigorated the field. Yet these newer GWAS methods have not replaced twin/family studies. In this review, we discuss the strengths and weaknesses of the two approaches with respect to characterizing genetic and environmental influences, measurement of behavioral phenotypes, and evaluation of causal models, with a particular focus on cognitive neuroscience. This discussion highlights how twin/family studies and GWAS complement and mutually reinforce one another.