Validation and extension of the endophenotype model in ADHD patterns of inheritance in a family study of inhibitory control.

OBJECTIVE: Endophenotypes, markers of underlying liability to psychiatric disorders, can improve the power to detect genetic risks relative to a complex clinical endpoint. Motor response inhibition is a prime candidate endophenotype in ADHD. In this study, the authors sought to extend the endophenotype model and further demonstrate its utility by investigating the parental origin of shared genetic risk in ADHD. METHOD: Inhibitory control was studied in children with ADHD, unaffected siblings, and their biological parents. Covariation in inhibitory control within families was investigated. Differential covariation as a function of parental sex was also studied. A number of validity criteria for inhibitory control as an endophenotype were assessed, including sensitivity to the disorder and presence in unaffected relatives. RESULTS: The results confirmed an inhibitory control deficit in children with ADHD as well as in their parents, independent of symptom severity in both generations. Inhibitory control ability in children was significantly predicted by the ability of their parents, particularly their fathers. CONCLUSIONS: These findings indicate that an inhibitory control deficit is a cognitive marker of genetic risk shared by parents and offspring. The endophenotype model is also extended by evidence of differential parental contributions to this risk, consistent with findings of parent-of-origin effects in the transmission of certain risk alleles observed in molecular analyses. The identification of these effects at the endophenotype level and their incorporation in genetic modeling can improve both linkage detection and localization of quantitative trait loci.

Genomic imprinting and human psychology: cognition, behavior and pathology.

Imprinted genes expressed in the brain are numerous and it has become clear that they play an important role in nervous system development and function. The significant influence of genomic imprinting during development sets the stage for structural and physiological variations affecting psychological function and behaviour, as well as other physiological systems mediating health and well-being. However, our understanding of the role of imprinted genes in behaviour lags far behind our understanding of their roles in perinatal growth and development. Knowledge of genomic imprinting remains limited among behavioral scientists and clinicians and research regarding the influence of imprinted genes on normal cognitive processes and the most common forms of neuropathology has been limited to date. In this chapter, we will explore how knowledge of genomic imprinting can be used to inform our study of normal human cognitive and behavioral processes as well as their disruption. Behavioural analyses of rare imprinted disorders, such as Prader-Willi and Angelman syndromes, provide insight regarding the phenotypic impact of imprinted genes in the brain, and can be used to guide the study of normal behaviour as well as more common but etiologically complex disorders such as ADHD and autism. Furthermore, hypotheses regarding the evolutionary development of imprinted genes can be used to derive predictions about their role in normal behavioural variation, such as that observed in food-related and social interactions.

Parent-of-origin effects in attention-deficit hyperactivity disorder.

The goal of the present study was to investigate parent-of-origin effects in attention-deficit hyperactivity disorder (ADHD). Parent-of-origin effects in ADHD may be due to differences in the relative quantity of risk factors transmitted by each parent. Alternatively, parent-of-origin effects may be produced by qualitative differences in the risks transmitted, such as those carried on the sex chromosomes or regulated by genomic imprinting. 60 children with maternal-only history of ADHD and 131 children with paternal-only history of ADHD were compared on three domains for which prior evidence suggested parent-of-origin effects may exist: core symptoms, disruptive behaviours and depression. Dependent variables were derived from previously validated, age-appropriate and standardized parent and teacher interviews and questionnaires. Depression levels were rated using the Child Depression Inventory. Consistent with previous research and the predictions derived from threshold models of ADHD etiology, the maternal history group received higher ratings of behavioural disorder (ADHD, conduct disorder and oppositional symptoms) than the paternal history group. Parent-of-origin effects were also observed for depression, with the paternal history group rating themselves as significantly more depressed than children in the maternal history group, particularly girls. Heightened paternal transmission relative to maternal is suggestive of genomic imprinting, and the interaction with proband sex indicates the involvement of the sex chromosomes or sex-specific physiological or hormonal factors. Interpretations of these data in terms of environmental and genetic factors, including epigenetic and sex-linked hypotheses, are explored.

The inheritance of cognitive skills: does genomic imprinting play a role?

Genomic imprinting refers to the differential expression of a gene based on parental origin. Animal and clinical studies have suggested that genomic imprinting is influential in brain development, with the maternal genome playing a disproportionate role in the development of the cortex. The present study investigated this phenomenon in a nonclinical human population, using intrafamilial correlations. Broadly consistent with predictions, it was found that abilities mediated by frontal, parietal, and temporal lobes, but not occipital lobes, were more closely correlated between children and mothers versus fathers. The implications of these findings for the prevailing theory of the evolution of genomic imprinting, and for the general study of genetics and behavior, are discussed.

Providing information at the point of care: educational diagnostic reports from a genetic testing service provider.

Strategies to facilitate the provisioning of genetic health-care services by primary care physicians will improve access to these services for the average patient while making the most efficient use of limited human and financial resources within the health-care system. Genetic laboratories have become a major source of information and consultation for clinicians ordering genetic tests. This article describes the development and evaluation of a program to provide physician-directed information from a molecular testing facility to assist physicians in selecting and counseling patients and interpreting genetic test results. Semi-structured telephone interviews were used to gather physicians' opinions about the utility of the program and the way in which the information was used in their practice. Forty-three percent of those interviewed were unfamiliar with some of the information provided, with test methodology and sensitivity/specificity most often identified as novel information. Fifty-two percent of pediatric specialists were unfamiliar with some aspect of the information Sheet, despite being the highest consumers of testing services in this sample. Pediatricians and pediatric specialists also rated the initiative highest in terms of its usefulness in their practice, followed by genetic specialists. Overall, physicians confirmed the utility of the program as an educational tool for themselves, and for other non-patient educational activities in which they are involved.