Irving I. Gottesman

Autism as a strongly genetic disorder : evidence from a British twin study

Two previous epidemiological studies of autistic twins suggested that autism was predominantly genetically determined, although the findings with regard to a broader phenotype of cognitive, and possibly social, abnormalities were contradictory. Obstetric and perinatal hazards were also invoked as environmentally determined aetiological factors. The first British twin sample has been re-examined and a second total population sample of autistic twins recruited. In the combined sample 60% of monozygotic (MZ) pairs were concordant for autism versus no dizygotic (DZ) pairs; 92% of MZ pairs were concordant for a broader spectrum of related cognitive or social abnormalities versus 10% of DZ pairs. The findings indicate that autism is under a high degree of genetic control and suggest the involvement of multiple genetic loci. Obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors. Few new cases had possible medical aetiologies, refuting claims that recognized disorders are common aetiological influences.

Socioeconomic Status Modifies Heritability of IQ in Young Children

Scores on the Wechsler Intelligence Scale for Children were analyzed in a sample of 7-year-old twins from the National Collaborative Perinatal Project. A substantial proportion of the twins were raised in families living near or below the poverty level. Biometric analyses were conducted using models allowing for components attributable to the additive effects of genotype, shared environment, and non-shared environment to interact with socioeconomic status (SES) measured as a continuous variable. Results demonstrate that the proportions of IQ variance attributable to genes and environment vary nonlinearly with SES. The models suggest that in impoverished families, 60% of the variance in IQ is accounted for by the shared environment, and the contribution of genes is close to zero; in affluent families, the result is almost exactly the reverse.

Twin studies of schizophrenia: From bow‐and‐arrow concordances to Star Wars Mx and functional genomics

Twin studies have been vital for establishing an important genetic contribution to the etiology of schizophrenia. The five newest studies since 1995 from Europe and Japan have confirmed earlier findings. They yielded probandwise concordance rates of 41-65% in monozygotic (MZ) pairs and 0-28% in dizygotic (DZ) pairs, and heritability estimates of approximately 80-85%. Twin studies are also valuable for investigating the etiological relationships between schizophrenia and other disorders, and the genetic basis of clinical heterogeneity within schizophrenia. Studies of discordant MZ pairs provide further insights into non-inherited factors that contribute to the multifactorial etiology of this disorder. More recently, twin studies have begun to be used to directly investigate molecular genetic and epigenetic processes underlying schizophrenia.

DNA methylation profiles in monozygotic and dizygotic twins

Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of ∼6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 × 10−294). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

Psychiatric endophenotypes and the development of valid animal models

Endophenotypes are quantifiable components in the genes‐to‐behaviors pathways, distinct from psychiatric symptoms, which make genetic and biological studies of etiologies for disease categories more manageable. The endophenotype concept has emerged as a strategic tool in neuropsychiatric research. This emergence is due to many factors, including the modest reproducibility of results from studies directed toward etiologies and appreciation for the complex relationships between genes and behavior. Disease heterogeneity is often guaranteed, rather than simplified, through the current diagnostic system; inherent benefits of endophenotypes include more specific disease concepts and process definitions. Endophenotypes can be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive or neuropsychological. Heritability and stability (state independence) represent key components of any useful endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors, resulting in units of analysis that are more amenable to being modeled in animals. We discuss the benefits of more direct interpretation of clinical endophenotypes by basic behavioral scientists. With the advent of important findings regarding the genes that predispose to psychiatric illness, we are at an important crossroads where, without anthropomorphizing, animal models may provide homologous components of psychiatric illness, rather than simply equating to similar (loosely analogized) behaviors, validators of the efficacy of current medications or models of symptoms. We conclude that there exists a need for increased collaboration between clinicians and basic scientists, the result of which should be to improve diagnosis, classification and treatment on one end and to increase the construct relevance of model organisms on the other.

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BackgroundSchizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease.DiscussionA vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal.There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems.SummaryA vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons.

Biological and genetic contributors to violence: Widom's untold tale

In her review of the literature on the intergenerational transmission of violent behaviors, Widom (1989a) addressed the social issues but omitted all references to the relevant biological and genetic literature. This addition to her review introduces studies of criminality, delinquency, and violence from a behavioral genetic standpoint. There is clear evidence for a genetic role in criminality and for a physiological basis for violent behavior. The inclusion of such genetic and biological evidence is necessary for a more complete understanding of the transmission of violence from one generation to another.

Just one g: consistent results from three test batteries

The concept of a general intelligence factor or g is controversial in psychology. Although the controversy swirls at many levels, one of the most important involves g’s identification and measurement in a group of individuals. If g is actually predictive of a range of intellectual performances, the factor identified in one battery of mental ability tests should be closely related to that identified in another dissimilar aggregation of abilities. We addressed the extent to which this prediction was true using three mental ability batteries administered to a heterogeneous sample of 436 adults. Though the particular tasks used in the batteries reflected varying conceptions of the range of human intellectual performance, the g factors identified by the batteries were completely correlated (correlations were .99, .99, and 1.00). This provides further evidence for the existence of a higher-level g factor and suggests that its measurement is not dependent on the use of specific mental ability tasks.

Severe Mental Disorders in Offspring With 2 Psychiatrically Ill Parents

BACKGROUND Studies of couples of psychiatric patients with children allow us to calculate the effects of double predispositions on morbid risk in the offspring, which is of interest for molecular genetic research and for genetic counseling. OBJECTIVE To determine the risks in offspring of receiving a diagnosis of schizophrenia, bipolar disorder, unipolar depressive disorder, or any diagnosis from parents who both have received a diagnosis of schizophrenia or bipolar disorder. DESIGN National register-based cohort study. SETTING Denmark. PARTICIPANTS A population-based cohort of 2.7 million persons born in Denmark, alive in 1968 or born later than 1968, with a register link to their mother and father and aged 10 years or older in 2007. MAIN OUTCOME MEASURE Risk of schizophrenia or bipolar disorder, calculated as cumulative incidences by age 52 years. RESULTS The risk of schizophrenia in 270 offspring of 196 parent couples who were both admitted to a psychiatric facility with a diagnosis of schizophrenia was 27.3% (increasing to 39.2% when schizophrenia-related disorders were included) compared with 7.0% in 13 878 offspring from 8006 couples with only 1 parent ever admitted for schizophrenia and 0.86% in 2 239 551 offspring of 1 080 030 couples with neither parent ever admitted. The risk of bipolar disorder was 24.9% in 146 offspring of 83 parent couples who were ever admitted with bipolar disorder (increasing to 36.0% when unipolar depressive disorder was included) compared with 4.4% in 23 152 offspring from 11 995 couples with only 1 parent ever admitted and 0.48% in 2 239 553 offspring of 1 080 030 couples with neither parent ever admitted. Risks of schizophrenia and bipolar disorder in offspring of couples with 1 parent with schizophrenia and the other with bipolar disorder were 15.6% and 11.7%, respectively. The maximal risks of any psychiatric disorders in the offspring of parents both with schizophrenia or both with bipolar disorder were 67.5% and 44.2%, respectively. CONCLUSIONS Derived risks may be informative for counseling. Patterns of transmission may support evolving assumptions about genetic overlap for traditional categories.

Heterogeneity of causes for delinquency and criminality: Lifespan perspectives

This review of family, twin, and adoption studies on offender behaviors points to the importance of a genetic predisposition as a partial explanation for criminality in some populations. Twin and adoption studies show that criminality increases with the presence of criminality in biological relatives; the environmental effects of having a criminal adoptive parent also increase the risk of adoptee criminality. Delinquency is described developmentally as a fairly typical phase for many adolescents. Because of the high base rate for delinquency, any genetic predisposition for offense behaviors may be difficult to uncover in adolescence. Three groups are differentiated that may aid in this detection: continuous antisocials are delinquents who continue to be criminal as adults; transitory delinquents are delinquents but not criminals; and late bloomers are criminals but not delinquents.