The inequity of education, health and care plan provision for children and young people with intellectual and developmental disabilities.

BACKGROUND: Children and young people (CYP) with intellectual and developmental disabilities (IDDs) have significant additional educational needs compared with the general population. In England, the government has established a system of education, health and care plans (EHCPs) to support children with special educational needs and disabilities, but disparities exist between the degree of need and the availability of support. We conducted a prospective UK national cohort study (IMAGINE) of children with rare pathogenic genomic variants, all of which are associated with IDD, to investigate associated neuropsychiatric risk. Subsequently, we obtained information from the UK's National Pupil Database on their educational progress through the state school system. We aimed to identify whether they had received EHCP provision and whether that support was associated with their family's socioeconomic status, region of domicile, ethnicity, sex, primary special educational needs (SEN) type, academic performance and mental health well-being. METHODS: We recruited 2738 CYP from England into the IMAGINE study between 2014 and 2019. The educational histories of the participants (6-28 years old, mean ± standard deviation = 14 ± 4 years, 56% male) were obtained from the Department for Education's National Pupil Database in 2021. Educational data included attainment scores from the Early Year Foundation Stage (<5 years) to key stage 4 (15-16 years). Each family was assigned an index of multiple deprivation (IMD) score based on their home address postcode. Parents or carers rated their child's emotional and behavioural adjustment on the Strengths and Difficulties Questionnaire (SDQ). The association between receiving an EHCP and the child's IMD score, eligibility for free school meals, English region of domicile, ethnicity, sex, primary SEN type, academic attainment and SDQ score was investigated. RESULTS: In this cohort, 78% of participants had received an EHCP. CYP living in the most deprived IMD deciles were substantially less likely to receive EHCP support than those in the least deprived decile, irrespective of their degree of intellectual developmental disability, academic performance or associated mental health problems. There were no sex differences. Children of Asian heritage were more likely to have been granted an EHCP than White children from equivalent IMD deciles. There were striking regional disparities. Participants living in London were significantly more likely to have been awarded an EHCP than participants living anywhere else in England, regardless of their IMD decile; those in the least deprived decile had almost 100% EHCP provision. CONCLUSIONS: This study found evidence for nationwide regional inconsistencies in the awarding of EHCP to CYP with significant intellectual impairments of known genetic aetiology. Disparities in funds available to education authorities could be a contributory factor. EHCP support was potentially influenced by how strongly a parent advocates for their child.

The COVID-19 pandemic's impact on worry and medical disruptions reported by individuals with chromosome 22q11.2 copy number variants and their caregivers.

BACKGROUND: The world has suffered immeasurably during the COVID-19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic. METHODS: The University of Pennsylvania COVID-19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages. RESULTS: A total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID-19 had the highest average endorsed worry, whilst currently having COVID-19 had the lowest rated worry. Total COVID-19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID-19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID-19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged. CONCLUSIONS: Widespread medical care disruptions and pandemic-related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long-term effects of COVID-19 worries, interruptions to care and hospital avoidance require further study.

Sleep problems and associations with psychopathology and cognition in young people with 22q11.2 deletion syndrome (22q11.2DS).

BACKGROUND: Young people with 22q11.2 deletion syndrome (22q11.2DS) are at high risk for neurodevelopmental disorders. Sleep problems may play a role in this risk but their prevalence, nature and links to psychopathology and cognitive function remain undescribed in this population. METHOD: Sleep problems, psychopathology, developmental coordination and cognitive function were assessed in 140 young people with 22q11.2DS (mean age = 10.1, s.d. = 2.46) and 65 unaffected sibling controls (mean age = 10.8, s.d.SD = 2.26). Primary carers completed questionnaires screening for the children's developmental coordination and autism spectrum disorder. RESULTS: Sleep problems were identified in 60% of young people with 22q11.2DS compared to 23% of sibling controls (OR 5.00, p < 0.001). Two patterns best-described sleep problems in 22q11.2DS: restless sleep and insomnia. Restless sleep was linked to increased ADHD symptoms (OR 1.16, p < 0.001) and impaired executive function (OR 0.975, p = 0.013). Both patterns were associated with elevated symptoms of anxiety disorder (restless sleep: OR 1.10, p = 0.006 and insomnia: OR 1.07, p = 0.045) and developmental coordination disorder (OR 0.968, p = 0.0023, and OR 0.955, p = 0.009). The insomnia pattern was also linked to elevated conduct disorder symptoms (OR 1.53, p = 0.020). CONCLUSIONS: Clinicians and carers should be aware that sleep problems are common in 22q11.2DS and index psychiatric risk, cognitive deficits and motor coordination problems. Future studies should explore the physiology of sleep and the links with the neurodevelopment in these young people.

Mental health and behavioural problems in children with XXYY: a comparison with intellectual disabilities.

BACKGROUND: The phenotype of children with XXYY has predominantly been defined by comparison to other sex chromosome aneuploidies trisomies affecting male children; however, the intellectual ability of children with XXYY is lower than children with other sex chromosome aneuploidies trisomies. It is not known to what extent the phenotype identified to date is specific to XXYY, rather than a reflection of lower IQ. This study evaluates the mental health and behaviour of children with XXYY, in comparison to children with intellectual disabilities of heterogeneous genetic origin. METHODS: Fifteen children with XXYY and 30 controls matched for age (4-14 years), sex and intellectual ability were ascertained from the IMAGINE ID study. IMAGINE ID participants have intellectual disabilities due to genetic anomalies confirmed by National Health Service Regional Genetic Centre laboratories. The mental health and behaviour of participants was examined with the Development and Well-being Assessment and the Strengths and Difficulties Questionnaire. RESULTS: Children with XXYY experienced significantly more frequent and intense temper outbursts than the control group. CONCLUSION: Our results suggest that temper outbursts may be specifically associated with the XXYY phenotype. These problems have a significant impact on the daily lives of boys with XXYY and their families. It is crucial to ensure that families are well supported to manage these difficulties.

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

16p11.2 Locus modulates response to satiety before the onset of obesity.

BACKGROUND: The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown. OBJECTIVE: This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs. METHODS: We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia. RESULTS: Response to satiety is gene dosage-dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI. CONCLUSIONS: These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence.

Alcohol misuse in bipolar disorder. A systematic review and meta-analysis of comorbidity rates.

AIMS: To assess the comorbidity rates of alcohol use disorders (AUDs) in bipolar disorder (BD) and to explore possible sources of heterogeneity. METHODS: Studies were identified through database searches. Meta-analytic techniques were employed to aggregate data on lifetime comorbidity and to explore possible sources of heterogeneity. Funnel plots were used to detect publication bias. RESULTS: In clinical studies, AUDs affected more than one in three subjects with BD. Significant heterogeneity was found, which was largely explained by the geographical location of study populations and gender ratio of participants. AUDs affected more than one in five women and two in five men. CONCLUSION: AUDs are highly prevalent in BD. Our study revealed a substantial heterogeneity across studies. Further research including control groups is needed. Patients with BD should be assessed for current and previous AUDs.

Familial transmission of depression and antisocial behavior symptoms: disentangling the contribution of inherited and environmental factors and testing the mediating role of parenting.

BACKGROUND: Genetic and environmental influences on child psychopathology have been studied extensively through twin and adoption designs. We offer a novel methodology to examine genetic and environmental influences on the intergenerational transmission of psychopathology using a sample of parents and children conceived through in vitro fertilization (IVF). METHOD: The sample included families with children born through IVF methods, who varied as to whether the child was genetically related or unrelated to the rearing mother and father (mother genetically related, n=434; mother genetically unrelated, n=127; father genetically related, n=403; father genetically unrelated, n=156). Using standardized questionnaires, mothers and fathers respectively reported on their own psychopathology (depression, aggression), their parenting behavior toward their child (warmth, hostility) and their child's psychopathology (depression, aggression). A cross-rater approach was used, where opposite parents reported on child symptoms (i.e. fathers reported on symptoms for the mother-child dyad, and vice versa). RESULTS: For mother-child dyads, a direct association between mother depression and child depression was observed among genetically unrelated dyads, whereas a fully mediated path was observed among genetically related dyads through mother-to-child hostility and warmth. For father-child dyads, direct and mediated pathways were observed for genetically related father-child dyads. For aggression, the direct association between parent aggression and child aggression was fully mediated by parent-to-child hostility for both groups, indicating the role of parent-to-child hostility as a risk mechanism for transmission. CONCLUSIONS: A differential pattern of genetic and environmental mediation underlying the intergenerational transmission of psychopathology was observed among genetically related and genetically unrelated father-child and mother-child dyads.

The links between prenatal stress and offspring development and psychopathology: disentangling environmental and inherited influences.

BACKGROUND: Exposure to prenatal stress is associated with later adverse health and adjustment outcomes. This is generally presumed to arise through early environmentally mediated programming effects on the foetus. However, associations could arise through factors that influence mothers' characteristics and behaviour during pregnancy which are inherited by offspring. METHOD: A 'prenatal cross-fostering' design where pregnant mothers are related or unrelated to their child as a result of in vitro fertilization (IVF) was used to disentangle maternally inherited and environmental influences. If links between prenatal stress and offspring outcome are environmental, association should be observed in unrelated as well as related mother-child pairs. Offspring birth weight and gestational age as well as mental health were the outcomes assessed. RESULTS: Associations between prenatal stress and offspring birth weight, gestational age and antisocial behaviour were seen in both related and unrelated mother-offspring pairs, consistent with there being environmental links. The association between prenatal stress and offspring anxiety in related and unrelated groups appeared to be due to current maternal anxiety/depression rather than prenatal stress. In contrast, the link between prenatal stress and offspring attention deficit hyperactivity disorder was only present in related mother-offspring pairs and therefore was attributable to inherited factors. CONCLUSIONS: Genetically informative designs can be helpful in testing whether inherited factors contribute to the association between environmental risk factors and health outcomes. These results suggest that associations between prenatal stress and offspring outcomes could arise from inherited factors and post-natal environmental factors in addition to causal prenatal risk effects.

Testing for gene x environment interaction effects in attention deficit hyperactivity disorder and associated antisocial behavior.

Gene x environment (G x E) interactions are increasingly thought to have substantial influence on the aetiology and clinical manifestations of complex disorders. In ADHD, although main effects of specific genetic variants and pre- or peri-natal variables have been reported and replicated using pooled analyses, few studies have looked at possible interactions. In a clinical sample of 266 children with ADHD, we tested for interaction between gene variants (in DRD4, DAT1, DRD5, and 5HTT) found to be associated with ADHD in pooled analyses and maternal smoking, alcohol use during pregnancy and birth weight. First, G x E effects on a diagnosis of ADHD were tested using conditional logistic regression analyses. Second, possible modifying effects of G x E on symptoms of associated conduct disorder and oppositional defiant disorder (ODD) were investigated using linear regression analysis. The sample size associated with each of the analyses differed as not each variant had been genotyped for each individual. No effects of G x E on ADHD diagnosis were observed. The results suggest that lower birth weight and maternal smoking during pregnancy may interact with DRD5 and DAT1 (birth weight only) in influencing associated antisocial behavior symptoms (ODD and conduct disorder). These preliminary findings showed no evidence of interaction between previously implicated variants in ADHD and specific environmental risk factors, on diagnosis of the disorder. There may be evidence of G x E on associated antisocial behavior in ADHD, but further investigation is needed.

No support for association between the dopamine transporter (DAT1) gene and ADHD.

Several groups have reported an association between the 10-repeat allele of a dopamine transporter (DAT1) 3'UTR VNTR variant and ADHD but the finding has not been universally observed. An association between DAT1 genotype and stimulant medication response has also been reported although again there are conflicting data. We tested the DAT1 3'VNTR and three SNPs in the putative promoter region of DAT1 for association with ADHD in 263 parent-proband trios. Analyses of genotypes, alleles, and haplotypes were performed using family-based association methods. Case-control analysis of the VNTR in 263 cases and 287 controls was also conducted. In addition, we tested for association between the VNTR marker and stimulant medication response. Comparing allele 10 versus all other alleles combined, no significant association was found with ADHD, using FBAT analysis (chi2 = 0.1 (df 1), P = 0.9, (odds ratio (OR) = 1.0, 95% CI 0.8-1.2), and case-control analysis (chi2 = 0.12 (df 2), P = 0.91). No evidence of association with any of the SNPs in the promoter region was found. Haplotype analysis was also non-significant (chi2 = 3.93, (df 9) global P = 0.85). Finally, no association was found between the DAT 1 VNTR and response to stimulant medication (chi2 = 1.63 (df 3) P = 0.65). We conclude that the 3' VNTR and three additional promoter variants in DAT1 do not appear to be associated with ADHD, or response to stimulant mediation in our sample.

Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour. A review.

Attention deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder which affects between 3% and 5% of school aged children. Despite much research, little is known regarding the aetiology of the disorder. Maternal cigarette smoking during pregnancy has been linked to a number of negative effects in offspring in infancy, childhood and even into adulthood and has been proposed as a possible risk factor for ADHD. The aim of this review was to discuss the evidence associating maternal smoking during pregnancy and ADHD as well as methodological issues concerning this association. A literature search using PubMed was employed using relevant keywords. The relevant reference sections of articles found were also searched. All English language studies published before June 2005 were assessed. A pooled odds ratio derived from case-control studies was also obtained. Despite methodological limitations, the majority of studies identify maternal smoking during pregnancy as a risk factor for ADHD behaviours. A pooled odds ratio indicates more than a two-fold increase in risk for a diagnosis of ADHD in those individuals whose mothers smoked during pregnancy (odds ratio 2.39, 95% confidence intervals 1.61, 3.52 P<0.001). Maternal smoking during pregnancy is a risk factor for ADHD behaviour and diagnoses, although the mechanisms through which such risks work is unknown.

Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD.

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5 x 10(-6)). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (chi(2)=5.7, P=0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset.

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.

Linkage disequilibrium mapping provides further evidence of a gene for reading disability on chromosome 6p21.3-22.

Linkage disequilibrium (LD) mapping was used to follow up reports of linkage between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22. Using a two-stage approach, we tested for association between RD and 22 microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage 2) parent/proband trios in which RD was rigorously defined. The most significant replicated associations were observed between combinations of markers D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2, P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001). The only two-marker association observed in both samples was with D6S422/1665 (P=0.01, 0.04). No single marker showed replicated association but D6S506 produced values of P=0.01 and 0.08 which were significant when combined (P=0.02). We observed weaker and less consistent evidence of association in a region of confirmed linkage to RD in previous studies. The most consistently significant haplotypic association D6S109/422/1665, showed association with single-word reading, spelling, phonological awareness, phonological decoding, orthographic accuracy and random automised naming, but not with vocabulary or Attention Deficit Hyperactivity Disorder. Our findings strongly support the presence of a gene contributing to RD in a region of chromosome 6 between markers D6S109 and D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.

Family history influence on drug abuse severity and treatment outcome.

Influence of parental alcohol/substance abuse on methadone maintenance therapy (MMT) outcome was examined in 164 DSM-III-R opioid dependent adults with no other current DSM Axis I disorder. Family history positive patients had more DSM-III-R opioid dependence symptoms and were more likely to be classified as severely dependent. However, when placed on identical daily doses of methadone (50 mg), they had lower rates of illicit opioid use but higher rates of cocaine use than family history negative patients. Both effects remained significant after adjusting for gender and race. These results suggest that common genetic factors may underlie both susceptibility to heroin dependence and response to therapeutic methadone treatment.

A twin study on sensation seeking, risk taking behavior and marijuana use.

The contribution of genetic and environmental factors to the covariation between risk-taking and marijuana use was assessed in adolescent twins. Genetic factors were found to significantly influence some traits (i.e. risk-taking attitude), while familial environmental factors were important for others (i.e. sexual promiscuity). For marijuana use, genetic and environmental factors were equally important; however, the association between risk taking and marijuana use may not be comparable for different behaviors. Results suggest that different etiological factors may underlie various risk taking traits which is relevant to both prevention efforts and attempts to identify genes involved in risk taking and shared genetic influences with substance use.

Environmental transmission of DSM-IV substance use disdorders in adoptive and step families.

BACKGROUND: One factor contributing to the 3- to 5-fold increase in risk for substance use disorders (SUDs) among children of alcoholics may be the rearing environment. These influences may include availability of substances, modeling of SUDs, inadequate parenting, or other factors. The contribution of parental environmental influences on offspring with SUDs may be estimated independently of genetic influences through assessment of adoptees raised by nonbiological parents. METHODS: Relative risk of SUDs was assessed in adult adoptees (N = 442) of alcoholic and nonalcoholic adoptive parents as well as in stepchildren (N = 1859) with alcoholic or nonalcoholic stepfathers who participated in the community-based National Longitudinal Alcohol Epidemiologic Survey (NLAES). RESULTS: Rearing by an alcoholic adoptive mother was associated with increased DSM-IV alcohol abuse. Rearing by an alcoholic adoptive father was predictive of adoptees' illicit drug use, as well as DSM-IV drug dependence. Rearing by an alcoholic stepfather was predictive of stepchild DSM-IV alcohol abuse, illicit drug use, and drug dependence, whereas an alcoholic stepmother was associated with increased illicit drug use in the stepchild. Alcoholism in adoptive parents or step parents did not increase risk for offspring DSM-IV alcohol dependence. In both adoptive and biological families, there was a subadditive interaction of mother by father alcoholism such that the rate of substance abuse when both parents were alcoholic was less than that expected based on the additive effects of each alcoholic parent. CONCLUSIONS: Rearing by an alcoholic parent had a greater influence on alcohol abuse by offspring than on alcohol dependence. The increased risk of proband illicit drug use and drug dependence associated with paternal alcoholism suggested nonspecificity of environmental transmission. Both maternal and paternal cultural transmission effects influenced offspring SUDs.