Abraham Reichenberg

The Familial Risk of Autism

IMPORTANCE Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved. OBJECTIVE To provide estimates of familial aggregation and heritability of ASD. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort including 2,049,973 Swedish children born 1982 through 2006. We identified 37,570 twin pairs, 2,642,064 full sibling pairs, 432,281 maternal and 445,531 paternal half sibling pairs, and 5,799,875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained. MAIN OUTCOMES AND MEASURES The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors. RESULTS In the sample, 14,516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100,000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64). CONCLUSIONS AND RELEVANCE Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.

Predicting schizophrenia patients' real-world behavior with specific neuropsychological and functional capacity measures.

BACKGROUND Significant neuropsychological (NP) and functional deficits are found in most schizophrenia patients. Previous studies have left questions as to whether global NP impairment or discrete domains affect functional outcomes, and none have addressed distinctions within and between ability and performance domains. This study examined the different predictive relationships between NP domains, functional competence, social competence, symptoms, and real-world behavior in domains of work skills, interpersonal relationships, and community activities. METHODS Two hundred twenty-two schizophrenic outpatients were tested with an NP battery and performance-based measures of functional and social competence and rated for positive, negative, and depressive symptoms. Case managers generated ratings of three functional disability domains. RESULTS Four cognitive factors were derived from factor analysis. Path analyses revealed both direct and mediated effects of NP on real-world outcomes. All NP domains predicted functional competence, but only processing speed and attention/working memory predicted social competence. Both competence measures mediated the effects of NP on community activities and work skills, but only social competence predicted interpersonal behaviors. The attention/working memory domain was directly related to work skills, executive functions had a direct effect on interpersonal behaviors, and processing speed had direct effects on all three real-world behaviors. Symptoms were directly related to outcomes, with fewer relationships with competence. CONCLUSIONS Differential predictors of functional competence and performance were found from discrete NP domains. Separating competence and performance provides a more precise perspective on correlates of disability. Changes in specific NP or functional skills might improve specific outcomes, rather than promoting global functional improvement.

Most genetic risk for autism resides with common variation

A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autisms genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.

Neuropsychological impairments in schizophrenia: Integration of performance-based and brain imaging findings.

Until recently, the dominant view was that schizophrenia patients have limited, if any, neuropsychological impairments, and those that are observed are only secondary to the florid symptoms of the disorder. This view has dramatically changed. This review integrates recent evidence demonstrating the severity and profile of neuropsychological impairments in schizophrenia. We present quantitative evaluation of the literature demonstrating that the most severe impairments are apparent in episodic memory and executive control processes, evident on a background of a generalized cognitive deficit. The neuropsychological impairments potentially represent genetic liability to the disorder, as similar, yet milder, impairments are evident in schizophrenia patients even before the onset of psychotic symptoms, as well as in the nonpsychotic relatives of schizophrenia patients. Corresponding cognitive neuroimaging literature on executive functions, episodic memory, and working memory in schizophrenia documenting abnormalities in frontal and medial temporal lobes is summarized, and current models integrating neuropsychological and neuroimaging data are discussed.

Static and Dynamic Cognitive Deficits in Childhood Preceding Adult Schizophrenia: A 30-Year Study

OBJECTIVE Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders? METHOD Participants were members of a representative cohort of 1,037 males and females born between 1972 and 1973 in Dunedin, New Zealand. Cohort members underwent follow-up evaluations at specific intervals from age 3 to 32 years, with a 96% retention rate. Cognitive development was analyzed and compared in children who later developed schizophrenia or recurrent depression as well as in healthy comparison subjects. RESULTS Children who developed adult schizophrenia exhibited developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory. These two premorbid cognitive patterns were not observed in children who later developed recurrent depression. CONCLUSIONS These findings suggest that the origins of schizophrenia include two interrelated developmental processes evident from childhood to early adolescence (ages 7-13 years). Children who will grow up to develop adult schizophrenia enter primary school struggling with verbal reasoning and lag further behind their peers in working memory, attention, and processing speed as they get older.

The neurocognitive signature of psychotic bipolar disorder.

BACKGROUND Psychotic bipolar disorder may represent a neurobiologically distinct subgroup of bipolar affective illness. We sought to ascertain the profile of cognitive impairment in patients with bipolar disorder and to determine whether a distinct profile of cognitive deficits characterizes bipolar patients with a history of psychosis. METHODS Sixty-nine outpatients with bipolar I disorder (34 with a history of psychotic symptoms and 35 with no history of psychosis) and 35 healthy comparison subjects underwent a comprehensive neurocognitive battery. All three groups were demographically matched. RESULTS Despite preserved general intellectual function, bipolar I patients overall showed moderate impairments on tests of episodic memory and specific executive measures (average effect size = .58), and moderate to severe deficits on attentional and processing speed tasks (average effect size = .82). Bipolar I patients with a history of psychosis were impaired on measures of executive functioning and spatial working memory compared with bipolar patients without history of psychosis. CONCLUSIONS Psychotic bipolar disorder was associated with differential impairment on tasks requiring frontal/executive processing, suggesting that psychotic symptoms may have neural correlates that are at least partially independent of those associated with bipolar I disorder more generally. However, deficits in attention, psychomotor speed, and memory appear to be part of the broader disease phenotype in patients with bipolar disorder.

Advancing Paternal Age and Bipolar Disorder

CONTEXT Advancing paternal age has been reported as a risk factor for neurodevelopmental disorders. OBJECTIVES To determine whether advanced paternal age is associated with an increased risk of BPD in the offspring and to assess if there was any difference in risk when analyzing patients with early-onset BPD separately. DESIGN A nationwide nested case-control study based on Swedish registers was performed. Risk for BPD in the offspring of older fathers was estimated using conditional logistic regression analysis controlling for potential confounding of parity, maternal age, socioeconomic status, and parental family history of psychotic disorders. SETTING Identification of 7,328,100 individuals and their biological parents by linking the nationwide Multigeneration Register and the Hospital Discharge Register. PARTICIPANTS A total of 13,428 patients with a BPD diagnosis on at least 2 separate hospital admissions was identified. Five healthy control subjects matched for sex and year of birth were randomized to each case. Main Outcome Measure Bipolar disorder based on ICD codes at discharge from hospital treatment. RESULTS An association between paternal age and risk for BPD in the offspring of older men was noted. The risk increased with advancing paternal age. After controlling for parity, maternal age, socioeconomic status, and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 (95% confidence interval [CI], 1.02-1.84) times more likely to be diagnosed as having BPD than the offspring of men aged 20 to 24 years. The maternal age effect was less pronounced. For early-onset (<20 years) cases, the effect of paternal age was much stronger (odds ratio, 2.63; 95% CI, 1.19-5.81), whereas no statistically significant maternal age effect was found. CONCLUSIONS Advanced paternal age is a risk factor for BPD in the offspring. The results are consistent with the hypothesis that advancing paternal age increases the risk for de novo mutations in susceptibility genes for neurodevelopmental disorders.

Excellent school performance at age 16 and risk of adult bipolar disorder: national cohort study

BACKGROUND Anecdotal and biographical reports suggest that bipolar disorder may be associated with high IQ or creativity, but evidence for any such connection is weak. AIMS To investigate possible associations between scholastic achievement and later bipolar disorder, using prospective data, in a whole-population cohort study. METHOD Using individual school grades from all individuals finishing compulsory schooling in Sweden between 1988 and 1997, we tested associations between scholastic achievement at age 15-16 and hospital admission for psychosis between ages 17 and 31, adjusting for potential confounders. RESULTS Individuals with excellent school performance had a nearly fourfold increased risk of later bipolar disorder compared with those with average grades (hazard ratio HR = 3.79, 95% CI 2.11-6.82). This association appeared to be confined to males. Students with the poorest grades were also at moderately increased risk of bipolar disorder (HR = 1.86, 95% CI 1.06-3.28). CONCLUSIONS These findings provide support for the hypothesis that exceptional intellectual ability is associated with bipolar disorder.

Cognitive performance in schizophrenia patients assessed before and following the first psychotic episode

BACKGROUND The purpose of this historical prospective study was to follow the cognitive impairment in schizophrenia from the premorbid period until shortly after the onset of the first psychotic episode within the same subjects. METHODS Forty-four first episode schizophrenia patients were enrolled in the study. Their cognitive performance was assessed as part of the Israeli Draft Board aptitude assessments at ages 16-17, when all were found to be in good mental health (first assessment) and again, following the manifestation of the first psychotic episode (second assessment). Forty-four healthy comparisons were also enrolled and tested twice, at the same ages as the patients. Both times, the assessments included four subtests assessing abstract reasoning (Raven Progressive Matrices-R), mental speed and concentration (Otis-R), verbal reasoning (Similarities-R), and mathematical abilities (Arithmetic-R). RESULTS A within group analysis did not reveal statistically significant changes between the first and the second assessment among the schizophrenia patients on any measure. However, a between group comparison of changes showed that relative to the healthy comparisons, schizophrenia patients deteriorated on the RPM-R (p=0.021) and Otis-R (p<0.001), but not on the Similarities-R and Arithmetic-R. Schizophrenia patients performed worse than comparisons in all four subtests on the first and second assessments (all p<0.01). CONCLUSIONS The results indicate that most of the cognitive impairment exhibited by first-episode schizophrenia patients precedes the first psychotic episode. A decline between ages 16 and 17 and the onset of psychosis is evident in some but not all cognitive functions.

Strong synaptic transmission impact by copy number variations in schizophrenia

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 × 10−7). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.