Joseph Marcus

Social Adjustment of Adolescents at Risk for Schizophrenia: The Jerusalem Infant Development Study

OBJECTIVE To better understand whether poor social adjustment, a core characteristic of schizophrenic illness, may also be an indicator of vulnerability in young people who are at genetic risk for schizophrenia, but who do not have schizophrenia. METHOD Between 1992 and 1996, 27 Israeli adolescents with a schizophrenic parent, 29 adolescents with no mentally ill parent, and 30 adolescents with a parent having a nonschizophrenic mental disorder were assessed on multiple domains of social adjustment measured using the Social Adjustment Inventory for Children and Adolescents and the Youth Self-Report. RESULTS Young people with a schizophrenic parent showed poor peer engagement, particularly heterosexual engagement, and social problems characterized by immaturity and unpopularity with peers. These social adjustment difficulties in youths at risk for schizophrenia could not be attributed solely to the presence of early-onset mental disorders, although problems were greater in those with disorders in the schizophrenia spectrum. Young people whose parents had other disorders showed different patterns of social maladjustment characterized by difficult, conflictual relationships with peers and family. CONCLUSION Adolescents at risk for schizophrenia have social deficits that extend beyond early-onset psychopathology and that may reflect vulnerability to schizophrenic disorder.

Overexpression of the Cytokine BAFF and Autoimmunity Risk

BACKGROUND Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug‐targetable pathways. METHODS Using case–control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus–specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence‐based fine mapping, cross‐population and cross‐phenotype analyses, and gene‐expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS A variant in TNFSF13B, encoding the cytokine and drug target B‐cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease‐risk allele was also associated with up‐regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion–deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up‐regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.)

Interpersonal behavior of children at risk for schizophrenia

Investigations of the childhood antecedents of adult schizophrenia may clarify our understanding of the etiology of the disease, provide guidelines for meaningful classification of subtypes of schizophrenic illness, point to strategies for identifying those individuals in need for early intervention, and suggest appropriate techniques for early intervention. Among the more salient characteristics of schizophrenic illness are disturbances in interpersonal relations, especially withdrawal from normal social interaction.

Maternal psychotropic medication and neonatal behavior

A sample of 29 psychiatrically ill women and a non-ill comparison group were recruited during pregnancy. Twelve of the ill mothers were receiving antipsychotic and anti-anxiety medication during the final trimester of pregnancy. The behavior of their infants was assessed at 3 and 14 days of age using the Brazelton Neonatal Behavioral Assessment Scale. Compared to infants of non-ill mothers and infants of ill nonmedicated mothers, infants whose mothers received antipsychotic drugs--particularly those in the phenothiazine family--showed a stable pattern of poor neonatal motor functioning that included tremulousness, hypertonicity, and poor motor maturity. It was speculated that this behavior was symptomatic of a neonatal abstinence or withdrawal syndrome.

A Longitudinal Study of Offspring Born to Methadone-Maintained Women. III. Effects of Multiple Risk Factors on Development at 4, 8, and 12 Months

Infants exposed to methadone in utero were compared to infants of drug-free women at 4, 8, and 12 months on two aspects of their behavior: motor coordination and attention. The purpose of this paper is to discuss how differences between the methadone and comparison infants were affected by other family and medical risk factors. No matter what the level of other risk factors, methadone infants showed poorer motor coordination at 4 months and poorer attention at 12 months as a group than comparison infants. Family risk factors, however, did modulate the strength and direction of differences between methadone and comparison infants. After 4 months, methadone infants continued to show poorer motor coordination than comparison infants only in families with poorer resources (such as low SES, maternal psychopathology and low intelligence, absence of father). Poorer early medical resources (pre- and perinatal complications) heightened the differences between methadone and comparison infants at early ages, but by the end of the first year no longer played a role in modulating the drug effect. The authors tentatively conclude that methadone exposure in utero has very limited teratological effects per se on the long-term development of infants, and that the pathology seen in some individual children is probably due to an interaction with other factors.

A tortoise–hare pattern seen in adapting structured and unstructured populations suggests a rugged fitness landscape in bacteria

Significance The “adaptive landscape” characterizes the relationship between genotype and fitness. As the landscape becomes more rugged, evolution can become more constrained. During the modern evolutionary synthesis, different views about the process of adaptation reflected different assumptions about landscape topography, which motivated the empirical assessment of adaptive landscapes in biological systems. Here, we describe how evolutionary patterns within experimental populations can yield information about landscape topography. Specifically, metapopulations of Escherichia coli are evolved under different patterns of migration. We find bacteria reach higher fitness and accumulate more mutations under restricted migration than unrestricted migration, which is consistent with a rugged topography. In this way, experimental manipulation of population structure can provide insight into fundamental evolutionary constraints. In the context of Wright’s adaptive landscape, genetic epistasis can yield a multipeaked or “rugged” topography. In an unstructured population, a lineage with selective access to multiple peaks is expected to fix rapidly on one, which may not be the highest peak. In a spatially structured population, on the other hand, beneficial mutations take longer to spread. This slowdown allows distant parts of the population to explore the landscape semiindependently. Such a population can simultaneously discover multiple peaks, and the genotype at the highest discovered peak is expected to dominate eventually. Thus, structured populations sacrifice initial speed of adaptation for breadth of search. As in the fable of the tortoise and the hare, the structured population (tortoise) starts relatively slow but eventually surpasses the unstructured population (hare) in average fitness. In contrast, on single-peak landscapes that lack epistasis, all uphill paths converge. Given such “smooth” topography, breadth of search is devalued and a structured population only lags behind an unstructured population in average fitness (ultimately converging). Thus, the tortoise–hare pattern is an indicator of ruggedness. After verifying these predictions in simulated populations where ruggedness is manipulable, we explore average fitness in metapopulations of Escherichia coli. Consistent with a rugged landscape topography, we find a tortoise–hare pattern. Further, we find that structured populations accumulate more mutations, suggesting that distant peaks are higher. This approach can be used to unveil landscape topography in other systems, and we discuss its application for antibiotic resistance, engineering problems, and elements of Wright’s shifting balance process.

Visualizing the geography of genetic variants

Abstract Summary One of the key characteristics of any genetic variant is its geographic distribution. The geographic distribution can shed light on where an allele first arose, what populations it has spread to, and in turn on how migration, genetic drift, and natural selection have acted. The geographic distribution of a genetic variant can also be of great utility for medical/clinical geneticists and collectively many genetic variants can reveal population structure. Here we develop an interactive visualization tool for rapidly displaying the geographic distribution of genetic variants. Through a REST API and dynamic front-end, the Geography of Genetic Variants (GGV) browser (http://popgen.uchicago.edu/ggv/) provides maps of allele frequencies in populations distributed across the globe. Availability and Implementation GGV is implemented as a website (http://popgen.uchicago.edu/ggv/) which employs an API to access frequency data (http://popgen.uchicago.edu/freq_api/). Python and javascript source code for the website and the API are available at: http://github.com/NovembreLab/ggv/ and http://github.com/NovembreLab/ggv-api/. Supplementary information Supplementary data are available at Bioinformatics online.

A Process Model for the Development of Schizophrenia

Less than two decades ago scientists interested in the etiology of schizophrenia were still vigorously debating the nature-nurture controversy, with many adhering to the view that the illness grew either out of a constitutional deficit or a pathological family environment. Today, virtually all researchers adopt interactional models that include both constitutional and environmental factors. Interactional models are most often expressed in diathesis-stress terms: Development of schizophrenia requires both a biological vulnerability (diathesis) and stressful life circumstances that facilitate expression of the illness. Modern debate within the field now primarily focuses on understanding the characteristics of the biological diathesis, the stressful environment, and their interaction. Scientists using diathesis-stress theories have employed several research strategies (Rosenthal 1970): (1) consanguinity studies exploring the distribution of illness among the relatives of schizophrenics, (2) twin studies comparing the concordance of schizophrenic illness in monozygotic and dizygotic twin pairs reared together or apart, (3) retrospective studies examining the premorbid behavior and development of schizophrenic parents, and (4) prospective studies of children at high risk for schizophrenia. The population most frequently followed in prospective high-risk studies has been offspring of schizophrenics. Biological offspring of schizophrenics who are reared by their parents are at extremely high risk for becoming schizophrenic themselves, approximately ten times greater risk than the general population. The present paper will make use of the Israeli High-Risk Study to test a diathesis-stress model for the transmission of schizophrenia. The goodness of fit of this model to the data will be explored using a simple decision tree data analytic approach.

Neurodevelopmental factors associated with schizotypal symptoms among adolescents at risk for schizophrenia

Schizophrenia has come to be viewed as a neurodevelopmental disorder that is characterized by genetic vulnerability, stressors during the prenatal period that may be marked by minor physical anomalies and neurobehavioral deficits that emerge in early development. Less is known about the neurodevelopmental origins of schizotypal personality symptoms. The present study examines schizotypal symptoms in Israeli adolescents (mean age = 16.79 years) who have not yet reached the developmental period during which first schizophrenic episode is most likely to emerge: 39 adolescent offspring of parents with schizophrenia, 39 offspring of parents with other psychiatric disorders, and 36 offspring of parents with no history of mental illness. The Semi-Structured Kiddie Interview for Personality Syndromes was used to assess cognitive-perceptual, interpersonal, and disorganized schizotypal symptoms. Interpersonal schizotypal symptoms were more prevalent in the schizophrenia offspring group than in the no-mental-illness offspring group. Among the schizophrenia offspring group, interpersonal, but not cognitive-perceptual, schizotypal symptoms were associated with minor physical anomalies, fine motor dyscoordination, and deficits in executive functioning during adolescence. Among young people whose parents did not have schizophrenia, cognitive-perceptual schizotypal symptoms were correlated with deficits in executive functioning. Adolescent schizotypal symptoms were associated with neurobehavioral symptoms measured during middle childhood in a subgroup of the sample that had been assessed prospectively. Finally, young people who had genetic risk for schizophrenia, minor physical anomalies, and neurobehavioral signs together were at markedly increased risk for symptoms of interpersonal schizotypal symptoms, compared to young people with one or none of these risk factors.

Population history of the Sardinian people inferred from whole-genome sequencing

The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of traits and diseases. The history of the Sardinian population has also been the focus of much research, and in recent ancient DNA (aDNA) studies, Sardinia has provided unique insight into the peopling of Europe and the spread of agriculture. In this study, we analyze whole-genome sequences of 3,514 Sardinians to address hypotheses regarding the founding of Sardinia and its relation to the peopling of Europe, including examining fine-scale substructure, population size history, and signals of admixture. We find the population of the mountainous Gennargentu region shows elevated genetic isolation with higher levels of ancestry associated with mainland Neolithic farmers and depleted ancestry associated with more recent Bronze Age Steppe migrations on the mainland. Notably, the Gennargentu region also has elevated levels of pre-Neolithic hunter-gatherer ancestry and increased affinity to Basque populations. Further, allele sharing with pre-Neolithic and Neolithic mainland populations is larger on the X chromosome compared to the autosome, providing evidence for a sex-biased demographic history in Sardinia. These results give new insight to the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.