Showing papers by "Michael Rutter published in 2010"

Functional impact of global rare copy number variation in autism spectrum disorders

Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

A genome-wide scan for common alleles affecting risk for autism

Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

I. investigating the impact of early institutional deprivation on development: background and research strategy of the english and romanian adoptees (era) study

Abstract: This monograph is concerned with the mid adolescent follow-up of a group of adoptees from Romania and from within the United Kingdom who were first assessed at the age of 4 years (or 6 years in the case of the oldest children). After describing the structure of this monograph, this chapter provides the background as it applied at the time that the study began, and then goes on to outline the overall research strategy and the measures relevant for the first assessment at age 4 years. The research literature with respect to other studies is considered here only in relation to the state of knowledge at the time our research began. Research findings since then are discussed separately in later chapters according to the topics considered in each individual chapter. This chapter then goes on to summarize, briefly, some of the key findings from the follow-ups undertaken up to the age of 11 years. The details of the measures, as relevant for the followup up to age 15 years, are provided in the second chapter.

Predictors of suicidality across the life span: the Isle of Wight study.

Abstract: Background Data from a representative community sample were used to explore predictors of lifetime suicidality and to examine associations between distal adolescent and more proximal adult risks. Method Data are from a midlife follow-up of the Isle of Wight study, an epidemiological sample of adolescents assessed in 1968. Ratings of psychiatric symptoms and disorder, relationships and family functioning and adversity were made in adolescence; adult assessments included lifetime psychiatric history and suicidality, neuroticism and retrospective reports of childhood sexual abuse and harsh parenting. Results A wide range of measures of childhood psychopathology, adverse experiences and interpersonal difficulties were associated with adult suicidality; associations were particularly strong for adolescent irritability, worry and depression. In multivariate analyses, substantial proportions of these effects could be explained by their association with adult psychopathology and neuroticism, but additional effects remained for adolescent irritability and worry. Conclusions Factors of importance for long-term suicidality risk are evident in adolescence. These include family and experiential adversities as well as psychopathology. In particular, markers of adolescent worry and irritability appeared both potent risks and ones with additional effects beyond associations with adult disorder and adult neuroticism.

5HTT genotype moderates the influence of early institutional deprivation on emotional problems in adolescence: evidence from the English and Romanian Adoptee (ERA) study

Abstract: Background: a common polymorphism in the serotonin transporter gene (SLC6A4, 5HTT) has been repeatedly shown to moderate the influence of childhood adversity and stressful life events on the development of psychopathology. Using data from the English and Romanian Adoptee Study, a prospective-longitudinal study of individuals (n = 125) exposed to severe early institutional deprivation (ID), we tested whether the effect of ID on adolescent emotional problems is moderated by 5HTT genotype and stressful life events in adolescence. Methods: emotional problems were assessed using questionnaire data (age 11), and on the basis of the CAPA diagnostic interview (age 15). Additionally, the number of stressful life events was measured. Results: there was a significant effect for genotype (p = .003) and a gene x environment interaction (p = .008) that was independent of age at testing. Carriers of the s/l and s/s genotype who experienced severe ID showed the highest emotional problem scores, while l/l homozygotes in the severe ID group showed the lowest overall levels. Furthermore, s/s carriers in the severe ID group who experienced a high number of stressful life events between 11 and 15 years had the largest increases in emotional problem scores, while a low number of stressful life events was associated with the largest decrease (4-way interaction: p = .05). Conclusions: the effects of severe early ID on emotional problems in adolescence are moderated by 5HTT genotype, and influenced by stressful life events in adolescence.

Deprivation-specific psychological patterns: Effects of institutional deprivation by the English and Romanian Adoptee Study Team

Abstract: The English and Romania Adoptees (ERA) study sought to capitalize on an invaluable ‘natural experiment’ in which there was a rapid, easily timed, transition from a profoundly depriving environment in Romanian institutions of the 1980’s and early 1990’s to a generally well functioning adoptive family in England. Moreover, the transition was not accompanied by the usual selective biases associated with admission to, and discharge from, the institution. Earlier reports considered findings on the cohort at 4, 6 and 11 years of age; here we extend the findings to age 15 years. Throughout the follow-up, we have been fortunate in having very low attrition, and we have endeavored to have multimodal methods of assessments. Thus, the measures have included detailed standardized interviews with both parents and their adopted offspring, questionnaires completed by parents, teachers and the young people themselves. In addition, there was systematic standardized psychometric testing of the young people, together with anthropometric measurements of height, weight and head circumference. DNA samples were obtained on the great majority of the adoptees, and a pilot brain imaging study was also undertaken. Our early findings indicated that the main outcomes that were strongly associated with institutional deprivation were unusual and distinctive: Namely, quasi-autism, disinhibited attachment, inattention/overactivity and cognitive impairment. We postulated that these might constitute possible deprivation-specific patterns. Accordingly, this monograph is focused on these postulated deprivation-specific patterns and their association with more general patterns of functioning and impairment. We began with a rigorous testing of the causal inference that these were truly due to institutional deprivation; the weight of evidence suggested that they were (albeit there were important changes in patterns and substantial improvement). Our findings showed a high degree of persistence to 16+ years of age, a remarkable persistence of the strong association with institutional deprivation, and pointers to the likelihood that there was coherence across the four separate deprivation-specific patterns. Moreover, the findings showed that psychosocial deprivation in the absence of subnutrition was accompanied by a major impairment in head growth (implying stunted brain growth) when the institutional deprivation lasted beyond the age of 6 months. Unlike height and weight, the head circumference continued to increase up to age 15 years, but still remained well below normal limits. Special attention was paid to the relationship between postulated deprivation-specific patterns and more ordinary and common disturbances of conduct, emotions, and peer relationships. Indeed the findings showed that all three of these patterns were associated with, and appeared to derive out of, earlier deprivation-specific features. However, the developmental course of the three features was markedly different. Emotional problems were unremarkable at 6 years, but increased over the 6 to 15 year age period. Insofar as could be judged, (usually) it was not that there was a late onset of them, but rather that its manifestations probably depended on a greater degree of maturation to become properly apparent. By contrast, an increase in conduct problems was beginning to be evident at 6 years, was clearly manifest at 11, and remained elevated at 15 years of age. It was most strongly associated with inattention/overactivity. The pattern for peer relationship problems was different yet again in that it was increased in frequency relative to the pooled comparison group, and was strongly associated with all four postulated deprivation-specific patterns. It was concluded that peer relationship problems constituted a sensitive index of social relationship problems and, therefore, are likely to be associated to some degree with any severe form of psychopathology, but especially with disorders in which difficulties in social relationships constitute such a prominent feature. Both conduct and emotional problems also showed associations with deprivation-specific features, but the developmental course of the two are strikingly different. Longitudinal data were crucial in identifying this difference. On the basis of cross-sectional findings, it had been claimed by others that the recovery of scholastic achievement lagged behind that of other cognitive functions. We did not find that but, again, the longitudinal analysis of within-individual change was essential in order to assess the possibility. Our results showed substantial heterogeneity in the specifics of cognitive patterns, but there was no single pattern that was specifically associated with institutional deprivation. Prior cross-sectional studies have typically reported complete catch-up in height and weight within 2 or 3 years after adoption. Our within-individual growth curves suggest that it is necessary to modify that conclusion. In keeping with previous research, we too found major catch-up in height and weight. What was different, however, was that we found a relative deceleration of growth between 11 and 15 years. The overall pattern of findings suggested that a significantly earlier puberty (found also in other studies of abuse and neglect) is likely to have played a role in both bringing about an earlier growth spurt and curtailing its duration. We had inadequate statistical power to test this in the way that we would have wished, but the possibility clearly warrants further research. Once again, the growth trajectory for head circumference was different, a deceleration was not evident and the catch-up to age 15 fell well short of population norms. Our measures of possible biological concomitants of deprivation-specific patterns were necessarily limited; however, two findings stood out. First, psychosocial deprivation, in the absence of overall subnutrition, had a major effect in constraining head growth (imaging data suggest that this was a reasonable index of brain growth) provided the deprivation continued beyond 6 months of age. Second, mediation analyses indicated that head circumference had a significant indirect role in the connection between institutional deprivation and deprivation-specific patterns. Because of the complexities of person-environment interplay, we finally sought to pull together findings on risk, causation, mediation and moderation. We conclude that, following a series of rigorous methodological checks, there was strong evidence for both the validity of deprivation-specific patterns, and their causation by institutional deprivation. However, our leads on possible moderating influences were necessarily more tentative. We see this as a high priority area and one that will require a broader range of measures (on genetic variations, but also on coping styles) than we were able to employ. Variations in the adoptive home environment did not seem to provide much of an effect, but something of a rethink is needed on how to conceptualize the measurement of relevant features.

Introduction to the Special Section on The Effects of Early Experience on Development

Abstract: One cardinal principle in developmental psychology is that early experience has a profound effect upon human development. Infants, once viewed as passive recipients of stimulation, are now understood to be active participants in the physical and social world that surrounds them. Learning takes place from a very early age and sets the course for trajectories of either adaptive or maladaptive behavior. A corollary to this principle is that there are certain periods during early development when experiences have a more significant effect than others. These periods, called sensitive or critical periods, are thought of as windows of opportunity during which certain types of experience have a foundational effect upon the development of skills or competencies. This special section of Child Development takes advantage of major advances in neuroscience, genetics, and improved developmental and statistical methods for studying the effects of early experience to provide readers with a broad range of review and empirical studies on this general topic. The special section is divided into seven parts: the first comprises two invited articles (Fox, Levitt, & Nelson, 2010; Meaney, 2010) that lay out important advances in neuroscience and molecular genetics. The second part provides five articles on fetal development and early experience. The third part contains three articles on perinatal experiences including low birth weight and long-term consequences on health and development, while the fourth part contains four articles on the effects of severe psychosocial deprivation, neglect, and abuse. The fifth part provides the reader with two articles on early experience and stress reactivity, while the sixth part presents three empirical articles examining basic mechanisms linking early experiences including poverty and adoption to behavior. Finally, Jack Shonkoff provides a commentary on the section with an eye toward thinking about the policy implications of the science. The importance of early experience and the identification of sensitive or critical periods have a long history within developmental research. Much of the early work was on the effects of early handling and stress reactivity by developmental psychobiologists such as Seymour Levine (Levine, 1957) and Victor Denenberg (Denenberg, 1964). Their work, primarily in the rodent, illustrated the effects of early handling on later learning and reactivity. The notion of critical periods was introduced to developmental psychology by ethologists, such as Hess and Lorenz (e.g., Hess, 1964) with work on imprinting. Thinking about the effects of early experience on development has been solidified with advances in neuroscience that have described the pattern of brain development during the early months and years of life and the role that experience has in shaping development. Two areas of research have changed the way we conceptualize the effects of early experience and the influences of biology and nurture. The first is the work in neuroscience, done almost exclusively in rodents and nonhuman primates, on the effects of early experience on brain development. The second area is the revolution in our thinking about the role of experience in the action of genes and molecular genetics. Neuroscience has provided an important foundation for our thinking about the role of early experience. Two lines of investigation are notable here. First, the descriptive work of Huttenlocher (Huttenlocher & Dabholkar, 1997) and Rakic (Granger, Tekaia, Le Sourd, Rakic, & Bourgeois,

III. Deprivation-specific psychological patterns.

Abstract: It has come to be generally accepted that the psychopathological effects of psychosocial stress and adversity are diagnostically nonspecific (McMahon, Grant, Compas, Thurm, & Ey, 2003). There is a good deal of supporting evidence in support of this assumption, even though it may be that the nonspecificity has been exaggerated through a failure to take account of comorbidity (Shanahan, Copeland, Costello, & Angold, 2008). Thus, although ‘‘natural experiments’’ have confirmed the reality of environmental mediation of causation, in the case of sexual abuse in childhood (Kendler, Kuhn, & Prescott, 2004), its risk effects span a range of diagnoses. In other words, knowing that someone has experienced sexual abuse does not enable a confident prediction at an individual level as to what psychopathology will be evident (see Glaser, 2008). Conversely, there is not a pattern of psychopathology that tells one that the disorder must have been due to sexual abuse. Much the same applies to other acute and chronic psychosocial stresses and adversities, such as physical abuse, exposure to family violence, exposure to severe family discord and conflict, and the experience of multiple negative life events carrying long-term threat. Accordingly, at the time that we started the study, our expectation, like those of other researchers, was that we would find the same with respect to institutional deprivation. It came very much as a surprise, therefore, that we found at age 6 no evident increase in the common varieties of emotional and behavioral problems that constitute the majority of mental health clinic referrals (Kreppner et al., 2007; Rutter et al., 1999). In sharp contrast, what we did find were four patterns that were strongly associated with institutional deprivation and that rarely occurred in other children within our sample. These comprised quasi-autism (Q-A; Rutter et al., 1999; Rutter, Kreppner et al., 2007), disinhibited attachment (DA; O’Connor, Bredenkamp, Rutter, MONOGRAPHS OF THE SOCIETY FOR RESEARCH IN CHILD DEVELOPMENT

IV. Developmental course of deprivation-specific psychological patterns: early manifestations, persistence to age 15, and clinical features.

Abstract: Chapter III (Kumsta et al.) presented findings on the designation of deprivation-specific psychological patterns (DSPs) and on the testing of the internal and external validity of the concept of a DSP. The starting point was the meeting of particular criteria at age 6 and persistence of impairment to age 11. In this chapter, we turn to our findings on the developmental course of DSPs. Because the postulate was that the DSP resulted from profound institutional deprivation, it is necessary to begin with findings on what the children were like at the time of leaving institutional care. The evidence is relevant to scientific question about continuities and discontinuities in individual differences in the children’s functioning in the institutions and the manifestation of DSPs that persisted at least up to age 11Fsome 71 years after adoption. It is also relevant to the practical question of whether prospective adoptive parents could identify children in the institutions who were likely, or unlikely, to show persisting DSPs postadoption. We next turn to the features of the four postulated DSPs between the ages of 6 and 11 yearsFstarting with quasi-autism (Q-A). The features as shown at age 6 were described in chapter III (Kumsta et al.) and will not, therefore, be repeated here. The emphasis is on both continuities and discontinuities (including change of pattern) over this age period. Chapter III (Kumsta et al.) indicated the criteria used for persistence to age 11, and here, by contrast, we focus on a qualitative description of what the children were like. In the case of the children with Q-A, we were able to use the detailed clinical assessments undertaken by M. R. together with the systematic ADOS and ADI-R findings. In addition, we have detailed findings on mental health and special educational service usage. In order to focus on MONOGRAPHS OF THE SOCIETY FOR RESEARCH IN CHILD DEVELOPMENT

Child and adolescent psychiatry: past scientific achievements and challenges for the future

Abstract: The worldwide history of scientific achievements in child and adolescent psychopathology is reviewed from the mid-twentieth century onwards. Attention is drawn, e.g., to diagnostic distinctions, measures of psychopathology, the several roles of epidemiological longitudinal studies, temperament and personality, developmental psychopathology, the use of 'natural experiments' to test causal inferences, environmental risks, the importance of gene-environment interplay, the relative coming together of initially diverse psychological therapies, the use of randomized-controlled trials to assess treatment efficacy, and the value and limitations of pharmacotherapy. The article ends with a look ahead to the most important opportunities and challenges for child and adolescent psychiatry, plus the hazards that need to be avoided.

X. conclusions: overview of findings from the era study, inferences, and research implications

Abstract: In this monograph, we have brought the findings of the English and Romanian Adoptee (ERA) study up to age 15 years and, in so doing, have focused especially on the question of whether there are deprivation-specific psychological patterns (DSPs) that differ meaningfully from other forms of psychopathology. For this purpose, our main analytic strategy was to compare the subgroup of young people who had received institutional care in Romania that persisted up to at least the age of 6 months and a pooled comparison group that comprised the remainder of the sample. In chapter II, we presented the evidence that there were no significant variations among the three subgroups that made up the pooled comparison group. A large proportion of this pooled comparison group came from the 52 individuals adopted before the age of 6 months from within the United Kingdom, who had not experienced institutional care or other major deprivation experiences. In addition, there were 45 children who had experienced institutional care that had ceased before the age of 6 months. Finally, there was a small group of 21 Romanian individuals who had come from a severely deprived background but who had not experienced institutional care. In the young people who experienced institutional deprivation, we found that a cut-off at 6 months marked the division between those without appreciable sequelae and those with a substantial proportion of persisting deficits. Because we found that the rate of deficits in the group who had experienced institutional care for 46 months did not vary according to the duration of institutional care, we pooled the entire group of individuals experiencing institutional care up to at least the age of 6 months. We found that these two pooled groups differed substantially and significantly in the rate of maladaptive outcomes. The details of the evidence justifying this pooling and a two-way comparison are provided in chapter II. Because of our interest in exploring the possibility of DSPs, our main subdivision within the above 6-month group was between those individuals showing the putative DSPs and those showing other forms of psychopathology or not showing deficits at all.

VII. Physical growth and maturation following early severe institutional deprivation: do they mediate specific psychopathological effects?

Abstract: Our previous work (Rutter et al., 2007) and the data reported in the preceding chapters of this monograph (chapter 4; Kreppner et al.) provide conclusive evidence of the persistent nature of the negative impact of early severe deprivation. Institutional deprivation, despite the good outcomes for many, was often associated with substantial impairment and disorder across a wide range of psychopathological domains at all follow-up ages. We have argued previously that this degree of persistence despite adoption into well functioning and nurturing families (chapter 8; Castle, Beckett, Rutter & Sonuga-Barke). Also, the considerable degree of continuity of problems seen at the level of individual cases (Kreppner et al., 2007), provides strong prima facie evidence that the effects of deprivation are associated with early established and fundamental neurobiological alterations (Mehta et al., 2009), although it remains to be seen what specific brain mechanisms are involved and whether different neurobiological components have specific effects on outcomes. There are a number of general mechanisms through which deprivation-related early adversity might operate to produce such long lasting effects (Rutter & O'Connor, 2004). Children who spent their early years in the Romanian institutions were exposed to multiple putative risks of diverse kinds (chapter 1; Rutter, Sonuga-Barke & Castle). The very poor quality and quantity of food provided, reflected in the substantial levels of subnutrition found amongst adoptees at the time of entry into the

IX. Risk, causation, mediation, and moderation.

Abstract: Throughout this monograph, there has been frequent reference to levels of risk, inference of causation, testing for mediating variables, and the need to consider possible moderating influences. In this chapter, we review what is meant by these concepts, and then seek to pull together the findings from the English and Romanian Adoptee (ERA) studies that were relevant for these issues. When the findings have been presented in detail in earlier chapters, we simply summarize the main salient points. However, with respect to possible genetic moderation of the effects of institutional deprivation, we present new data because these were not considered in earlier chapters. There was a time when most developmental research, particularly that dealing with social development, moved blithely ahead using cross-sectional studies to investigate developmental processes without consideration of the multiple complex ways in which these processes may work together or separately. That is no longer acceptable (Kraemer et al., 1997; Kraemer, Stice, Kazdin, Offord, & Kupfer, 2001; Murray, Farrington, & Eisner, 2009; Rutter, 1988, 2009). Not only must the various processes, and their interplay, be clearly conceptualized, but also it will be essential to pit different refutable causal hypotheses against each other (Lahey, D'Onofrio, & Waldman, 2009; Rutter, 2003, 2006b).

A tribute to Lee Nelken Robins: from colleagues and friends

Abstract: On September 25, 2009, Lee Nelken Robins, Ph.D., professor emeritus of Social Science in Psychiatry at Washington University School of Medicine in St. Louis, died peacefully at her home, after a long battle with cancer. On that day, the field lost a world leader in psychiatric epidemiology. Born August 29, 1922, in New Orleans, Robins earned a doctoral degree from Harvard University/Radcliffe College in 1951. She joined the faculty at Washington University School of Medicine in 1954 as a research assistant in psychiatry and rose to the rank of full professor in 1968. From 1957 until 1963, she also served as a lecturer and an adjunct associate professor of Sociology; from 1969 to 1991, she served as professor of Sociology, and was professor in the Program for Social Thought and Analysis from 1991 until her retirement from the University in 2001. She founded and directed the Master’s Program in Psychiatric Epidemiology at the School of Medicine, a one of a kind graduate program for mental health and addiction researchers that flourishes today. In addition to her own prolific and significant work, she collaborated with her husband Eli Robins, a major figure in A note from the editor in chief: Lee Robins was for several years on the board of Social Psychiatry, as this journal then was, and her work has continuing and central relevance to our subject. This is clear from what is written below, which serves as a journey round scientific developments of crucial importance in the last five decades. On a personal note, it is strange to read about this greatly distinguished woman and her legacy, and then to remember the down-to-earth person I used to kidnap and take to the pub whenever she was over at the Institute of Psychiatry. She had a most un-academic laugh. She and Eli were kindness itself when I was asked to give the 1987 Eli Robins lecture in St. Louis. We are pleased and honored to publish this selection of tributes to the late Lee Robins.

Mediating Mechanisms and Emotions

Abstract: Kagan successfully forces us to re-examine our assumptions and concepts regarding the broad field of “emotion.” His postulated four phases start with the brain state provoked by some stimulus. While that constitutes a reasonable starting point, the specificity of the brain qualities provoked by different types of stimuli remains uncertain. The recommendations on the way forward are the least satisfying aspects of this article. Integration would have been helped by some consideration of the role of animal models, of the ways in which genes operate, and of the multiple varieties of gene—environment interplay.