Kristen C. Jacobson

Distinct Genetic Influences on Cortical Surface Area and Cortical Thickness

Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51-59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.

Developmental Trajectories of Substance Use From Early Adolescence to Young Adulthood: Gender and Racial/Ethnic Differences

PURPOSE The current study examined gender and racial/ethnic (Hispanics, non-Hispanic Caucasians, non-Hispanic African Americans, and non-Hispanic Asians) differences in developmental trajectories of alcohol use, heavy drinking, smoking, and marijuana use from early adolescence to young adulthood using a nationally representative sample. METHODS Participants from the National Longitudinal Study of Adolescent Health (N = 20,160) reported rates of alcohol use, heavy drinking, smoking, and marijuana use between the ages of 12 and 34 years. Data analyses were completed using longitudinal multilevel modeling analyses. RESULTS Levels of substance use increased from early adolescence to mid-20s, and then declined thereafter. Females showed higher levels of substance use in early adolescence, although males exhibited greater changes overtime and higher levels of use in mid-adolescence and early adulthood. Overall, Hispanic youth had higher initial rates of substance use, whereas Caucasian adolescents showed higher rates of change and had the highest levels of substance use from mid-adolescence through the early 30s. Racial/ethnic differences largely disappeared after age 30, except that African Americans showed higher final levels of smoking and marijuana use than the other racial/ethnic groups. Results provide evidence for both similarities and differences in general patterns of development and in gender and racial/ethnic differences across different forms of substance use. CONCLUSIONS Findings from the current study suggest that the critical periods for intervention and prevention of substance use may differ across gender and race/ethnicity, and that future research needs to identify common and unique mechanisms underlying developmental patterns of different forms of substance use.

Genetic and Environmental Influences on the Relationships between Family Connectedness, School Connectedness, and Adolescent Depressed Mood: Sex Differences.

This study investigated (a) genetic and environmental contributions to the relationship between family and school environment and depressed mood and (b) potential sex differences in genetic and environmental contributions to both variation in and covariation between family connectedness, school connectedness, and adolescent depressed mood. Data are from 2,302 adolescent sibling pairs (mean age = 16 years) who were part of the National Longitudinal Study of Adolescent Health. Although genetic factors appeared to be important overall, model-fitting analyses revealed that the best-fitting model was a model that allowed for different parameters for male and female adolescents. Genetic contributions to variation in all 3 variables were greater among female adolescents than male adolescents, especially for depressed mood. Genetic factors also contributed to the correlations between family and school environment and adolescent depressed mood, although, again, these factors were stronger for female than for male adolescents.

Sex differences in the genetic and environmental influences on the development of antisocial behavior

The present study uses a population-based sample of 6.806 adult twins from same-sex and opposite-sex twin pairs to examine sex differences in the underlying genetic and environmental architecture of the development of antisocial behavior (AB). Retrospective reports of AB during three different developmental periods were obtained: prior to age 15 years (childhood), age 15-17 years (adolescent), and age 18 years and older (adult). Structural equation modeling analyses revealed that there was no evidence for sex-specific genetic or sex-specific shared family environmental influences on the development of AB; that is, the types of genetic and environmental influence were similar for males and females. For both sexes, a model that allowed for genetic influences on adolescent and adult AB that were not shared with childhood AB fit better than a model with a single genetic factor. In contrast, shared environmental influences on adolescent and adult AB overlapped entirely with shared environmental influences on childhood AB. Genetic factors played a larger role in variation in childhood AB among females, whereas shared environmental factors played a larger role among males. However, heritability of AB increased from childhood to adolescence and adulthood for both sexes, and the magnitude of genetic and environmental influences on adolescent and adult AB was approximately equal across sex. We speculate that sex differences in timing of puberty may account for the earlier presence of genetic effects among females.

Multivariate genetic analysis of sex limitation and G x E interaction.

Sex-limited expression of genetic or environmental factors occurs in two basic forms. First, the effects of a factor may be larger on one sex than on another, which is known as scalar sex limitation. Second, some factors may have an effect on one sex but not on the other, which is called nonscalar sex limitation. In the classical twin study, scalar sex-limited effects cause same-sex male and same-sex female twin correlations to differ. Nonscalar sex-limited effects would cause the correlations between opposite-sex pairs of relatives to be lower than would be expected from the correlations between relatives of the same sex. One approach to modeling such effects is to allow the genetic correlation between opposite-sex dizygotic twins to be less than one-half; another is to allow the common environment correlation for opposite-sex pairs to be less than unity. Extension of this approach to the multivariate case is not straightforward. Direct extension of the Cholesky decomposition such that each Cholesky factor is allowed to correlate less than one-half in opposite-sex pairs yields a model where the order of the variables can change the goodness-of-fit of the model. It is shown that similar problems exist with a variety of multivariate and longitudinal models, and in a variety of models of genotype x environment interaction. Several solutions to these problems are described.

Genes, Environment, and Time: The Vietnam Era Twin Study of Aging (VETSA)

The Vietnam Era Twin Study of Aging (VETSA) is a large-scale investigation of cognitive aging from middle to later age. The intended sample of 1440 twin subjects is recruited from the Vietnam Era Twin Registry (VETR), a registry of middle-aged male-male twin pairs who both served in the military during the Vietnam conflict (1965-1975). VETSA employs a multitrait multimethod approach to cognitive assessment to focus on the genetic and environmental contributions to cognitive processes over time, as well as the relative contributions to cognitive aging from health, social, personality, and other contextual factors. The cognitive domains of episodic memory, working memory, abstract reasoning, and inhibitory executive functioning are assessed through neuropsychological testing. In addition, VETSA obtains the participants score on the Armed Forces Qualification Test, taken at the time of induction into the military around age 20 years, and re-administers the test. Two other projects--VETSA Cortisol and VETSA Magnetic Resonance Imaging--are also in progress using subsamples of the VETSA twins. Prior waves of data collection by VETSA investigators using the VETR have provided historical data on physical and mental health, while future waves of VETSA data collection are planned every 5 years. These methods will provide data on multiple phenotypes in the same individuals with regard to genetic and environmental contributions to cognitive functioning over time, personality and interpersonal risk and protective factors, stress and cortisol regulation, and structural brain correlates of aging processes.

Gene-Environment Interplay in Common Complex Diseases: Forging an Integrative Model—Recommendations From an NIH Workshop

Although it is recognized that many common complex diseases are a result of multiple genetic and environmental risk factors, studies of gene‐environment interaction remain a challenge and have had limited success to date. Given the current state‐of‐the‐science, NIH sought input on ways to accelerate investigations of gene‐environment interplay in health and disease by inviting experts from a variety of disciplines to give advice about the future direction of gene‐environment interaction studies. Participants of the NIH Gene‐Environment Interplay Workshop agreed that there is a need for continued emphasis on studies of the interplay between genetic and environmental factors in disease and that studies need to be designed around a multifaceted approach to reflect differences in diseases, exposure attributes, and pertinent stages of human development. The participants indicated that both targeted and agnostic approaches have strengths and weaknesses for evaluating main effects of genetic and environmental factors and their interactions. The unique perspectives represented at the workshop allowed the exploration of diverse study designs and analytical strategies, and conveyed the need for an interdisciplinary approach including data sharing, and data harmonization to fully explore gene‐environment interactions. Further, participants also emphasized the continued need for high‐quality measures of environmental exposures and new genomic technologies in ongoing and new studies. Genet. Epidemiol. 35: 217‐225, 2011.  © 2011 Wiley‐Liss, Inc.

Genes Determine Stability and the Environment Determines Change in Cognitive Ability During 35 Years of Adulthood

Previous research has demonstrated stability of cognitive ability and marked heritability during adulthood, but questions remain about the extent to which genetic factors account for this stability. We conducted a 35-year longitudinal assessment of general cognitive ability using the Armed Forces Qualification Test administered to 7,232 male twins in early adulthood and readministered to a subset of 1,237 twins during late middle age. The proportion of variance in cognitive functioning explained by genetic factors was .49 in young adulthood and .57 in late middle age. The correlation between the two administrations was .74 with a genetic correlation of 1.0, indicating that the same genetic influences operated at both times. Genetic factors were primarily responsible for stability, and nonshared environmental factors were primarily responsible for change. The genetic factors influencing cognition may change across other eras, but the same genetic influences are operating from early adulthood to late middle age.

A genetically informative developmental study of the relationship between conduct disorder and peer deviance in males

BACKGROUND Conduct disorder (CD) and peer deviance (PD) both powerfully predict future externalizing behaviors. Although levels of CD and PD are strongly correlated, the causal relationship between them has remained controversial and has not been examined by a genetically informative study. METHOD Levels of CD and PD were assessed in 746 adult male-male twin pairs at personal interview for ages 8-11, 12-14 and 15-17 years using a life history calendar. Model fitting was performed using the Mx program. RESULTS The best-fit model indicated an active developmental relationship between CD and PD including forward transmission of both traits over time and strong causal relationships between CD and PD within time periods. The best-fit model indicated that the causal relationship for genetic risk factors was from CD to PD and was constant over time. For common environmental factors, the causal pathways ran from PD to CD and were stronger in earlier than later age periods. CONCLUSION A genetically informative model revealed causal pathways difficult to elucidate by other methods. Genes influence risk for CD, which, through social selection, impacts on the deviance of peers. Shared environment, through family and community processes, encourages or discourages adolescent deviant behavior, which, via social influence, alters risk for CD. Social influence is more important than social selection in childhood, but by late adolescence social selection becomes predominant. These findings have implications for prevention efforts for CD and associated externalizing disorders.

The structure of schizotypy: relationships between neurocognitive and personality disorder features in relatives of schizophrenic patients in the UCLA Family Study

Schizotypal personality features and certain neurocognitive deficits have been shown to aggregate in the relatives of schizophrenic patients, supporting the view that both are likely to reflect genetic contributions to liability to schizophrenia. Within the relatives of schizophrenic patients, however, the interrelationships between these potential indicators of liability to schizophrenia are not well known. Using data from the UCLA Family Study, we examine the interrelationships between personality disorder symptoms and neurocognitive functioning in nonpsychotic first-degree relatives of schizophrenic patients. Factor analyses indicate that several dimensions of schizotypy can be identified. A neurocognitive dysfunction dimension includes loadings from measures of sequential visual conceptual tracking, rapid perceptual encoding and search, and focused, sustained attention as well as the rating of odd and eccentric behavior from schizotypal personality disorder. Other aspects of schizotypal personality disorder form separate positive schizotypy and negative schizotypy dimensions. These analyses support the view that schizotypy is multidimensional in relatives of schizophrenic patients and indicate that neurocognitive deficits in perception and attention are associated with particular schizotypal personality features.