Showing papers by "Carol E. Franz published in 2011"

Genetic and Environmental Contributions to Regional Cortical Surface Area in Humans: A Magnetic Resonance Imaging Twin Study

Abstract: Cortical surface area measures appear to be functionally relevant and distinct in etiology, development, and behavioral correlates compared with other size characteristics, such as cortical thickness. Little is known about genetic and environmental influences on individual differences in regional surface area in humans. Using a large sample of adult twins, we determined relative contributions of genes and environment on variations in regional cortical surface area as measured by magnetic resonance imaging before and after adjustment for genetic and environmental influences shared with total cortical surface area. We found high heritability for total surface area and, before adjustment, moderate heritability for regional surface areas. Compared with other lobes, heritability was higher for frontal lobe and lower for medial temporal lobe. After adjustment for total surface area, regionally specific genetic influences were substantially reduced, although still significant in most regions. Unlike other lobes, left frontal heritability remained high after adjustment. Thus, global and regionally specific genetic factors both influence cortical surface areas. These findings are broadly consistent with results from animal studies regarding the evolution and development of cortical patterning and may guide future research into specific environmental and genetic determinants of variation among humans in the surface area of particular regions.

Presence of ApoE ε4 allele associated with thinner frontal cortex in middle age.

Abstract: The presence of an ApoE e4 allele (e4+) increases the risk of developing Alzheimer's disease (AD). Previous studies support an adverse relationship between e4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an e2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51-59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (e3/3, e2/3, e3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the e3/3 group, the e3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of e4 status on any temporal lobe measures. The e2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the e3/3 group. The ApoE e4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of e4-related effects. The presence of the e2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age- and disease-related mediation of the influence of ApoE allele status.

A 35-Year Longitudinal Assessment of Cognition and Midlife Depression Symptoms: The Vietnam Era Twin Study of Aging

Abstract: Objective To determine whether early adult cognitive ability is a risk factor for depressive symptoms in midlife and how genetic and environmental influences explain the association and to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife. Design A 35-year longitudinal and cross-sectional twin study of cognitive aging. Setting Large multicenter study in the United States. Participants One thousand two hundred thirty-seven male twins aged 51 to 60 years. Measurements At the age of 20 years and midlife, participants completed the same version of a general cognitive ability test (Armed Forces Qualification Test [AFQT]). Midlife testing included an extensive neurocognitive protocol assessing processing speed, verbal memory, visual-spatial memory, working memory, executive function, and visual-spatial ability. Participants completed the Center for Epidemiologic Studies Depression Scale before cognitive testing and provided health and life style information during a medical history interview. Results Lower age 20 AFQT scores predicted higher levels of depressive symptoms at age 55 years (r = −0.16,p Conclusion Results suggest that low cognitive ability is a risk factor for depressive symptoms; this association is partly due to shared genetic influences. Crosssectional analyses indicate that the association between depressive symptoms and performance is not linked to specific cognitive domains.

Genetic patterns of correlation among subcortical volumes in humans: results from a magnetic resonance imaging twin study.

Abstract: Little is known about genetic influences on the volume of subcortical brain structures in adult humans, particularly whether there is regional specificity of genetic effects. Understanding patterns of genetic covariation among volumes of subcortical structures may provide insight into the development of individual differences that have consequences for cognitive and emotional behavior and neuropsychiatric disease liability. We measured the volume of 19 subcortical structures (including brain and ventricular regions) in 404 twins (110 monozygotic and 92 dizygotic pairs) from the Vietnam Era Twin Study of Aging and calculated the degree of genetic correlation among these volumes. We then examined the patterns of genetic correlation through hierarchical cluster analysis and by principal components analysis. We found that a model with four genetic factors best fit the data: a Basal Ganglia/Thalamus factor; a Ventricular factor; a Limbic factor; and a Nucleus Accumbens factor. Homologous regions from each hemisphere loaded on the same factors. The observed patterns of genetic correlation suggest the influence of multiple genetic influences. There is a genetic organization among structures which distinguishes between brain and cerebrospinal fluid spaces and between different subcortical regions. Further study is needed to understand this genetic patterning and whether it reflects influences on early development, functionally dependent patterns of growth or pruning, or regionally specific losses due to genes involved in aging, stress response, or disease.

Genetic architecture of learning and delayed recall: a twin study of episodic memory.

Abstract: Episodic memory, the ability to accurately recall details from one’s daily experiences, is an essential cognitive process that is heavily impacted by normal cognitive aging, and is associated with a host of neurological and psychiatric conditions (Airaksinen, Larsson, Lundberg, & Forsell, 2004; Butters, Delis, & Lucas, 1995; Cirillo & Seidman, 2003; Mariani, Monastero, & Mecocci, 2007; Nilsson, 2003; Petersen et al, 1999; Schaie, 1996; Zec, 1993) Like most measures of cognitive functioning, episodic memory appears to be heritable (ie, a significant proportion of its variance is attributable to genetic factors), with the majority of twin studies conducted to date reporting estimates of its genetic influence in the range of 30 to 60 (Alarcon, Plomin, Fulker, Corley, & DeFries, 1998; T J Bouchard, Segal, & Lykken, 1990; Finkel, Pedersen, & McGue, 1995; Johansson et al, 1999; McClearn et al, 1997; Pedersen, Plomin, Nesselroade, & McClearn, 1992; Swan et al, 1999; Thapar, Petrill, & Thompson, 1994; Volk, McDermott, Roediger, & Todd, 2006) Yet despite the significant degree to which behavior genetics researchers have studied episodic memory, there remain a number of fundamental aspects of its underlying genetic structure that have yet to be explored Among these is the genetic relationship between learning and delayed recall Experimental and clinical perspectives of episodic memory have long viewed the construct as a complex set of processes that include the ability of the individual to initially attend to, encode, and then later retrieve information (Baddeley, 2004; Butters et al, 1995; Erickson & Scott, 1977; Luria, 1973; Squire, Knowlton, & Musen, 1993; Tulving, 1983) On tests of episodic memory these processes can be represented by measures of learning ability, which capture both the acquisition and immediate retrieval of information, and measures of delayed recall, which capture only retrieval processes The relationship between learning and delayed recall has proven to be critical in the assessment of memory disorders, for instance helping to distinguish between encoding and retrieval deficits (Butters et al, 1995) However, in non-clinical populations the two measures have been found to correlate strongly with one another and have frequently been shown to load onto the same higher-order factor (Delis, Freeland, Kramer, & Kaplan, 1988; Delis, Jacobson, Bondi, Hamilton, & Salmon, 2003; Millis, Malina, Bowers, & Ricker, 1999) Such findings have led to debate as to whether learning and delayed recall capture different cognitive constructs or whether they are actually redundant measures of the same process (Delis et al, 2003; Nee, Berman, Moore, & Jonides, 2008; Ranganath & Blumenfeld, 2005) From a genetic perspective, strong phenotypic relationships provide little information about the degree of shared genetic influences between measures For instance, a recent study by our group demonstrated that while measures from a test of planning and problem-solving, the Tower of London, loaded onto a single phenotypic factor, examination of the genetic influences revealed the presence of two genetic factors, one accounting for speed and the other for efficiency (Kremen et al, 2009) Thus, although learning and delayed recall are highly correlated in non-clinical populations, it is unclear whether this means that they share the same underlying genetic factors Clarification of this relationship may provide valuable insights into the processes that are involved in episodic memory, as well as the variety of conditions that result in episodic memory impairment Determining whether learning and delayed recall are, at least in part, influenced by non-shared genetic factors would provide support for the view that these are indeed non-redundant aspects of episodic memory, and establish the presence of distinct biological influences that are not ordinarily observable This may in turn improve the ability of researchers to identify processes, either biological or environmental, that drive age-related changes in memory, as well as changes observed in AD and MCI If, however, these measures share all of their genetic influences then models of how episodic memory changes over the course of normal aging or disease progression may have to be reconsidered With respect to gene association studies, identifying the presence of unique genetic influences for either learning or delayed recall would enable researchers to refine their phenotypes of interest by filtering out the effects of variables that contribute superfluous genetic influences, ultimately leading to a more targeted search for the genes involved To date, behavior genetics studies of episodic memory, unlike the experimental and clinical traditions, have been based largely on single measures of performance and have consequently ignored the relationship between learning and delayed recall In order to fully elucidate the genetic relationship between these measures a multivariate application of the classical twin design is required Whereas univariate twin analyses decompose the variance of a phenotype of interest into genetic and environmental components, multivariate twin analyses allow for the further decomposition of the covariance between multiple phenotypes (Neale & Cardon, 1992) As a result, the degree to which observed relationships are driven by genetic and/or environmental influences can be determined, as can the degree to which latent genetic and environmental influences of the phenotypes are predictive of one another (ie genetic and environmental correlations) Multivariate twin analyses also allow for genetically informative factor models to be tested, models that allow for sources of common genetic and environmental influences to be constrained into simplified structures while simultaneously capturing the degree to which the phenotypes of interest are influenced by unique, or variable-specific, genetic and environmental influences While no multivariate twin analysis of learning and delayed recall has been conducted to date, one prior twin study does warrant mention Utilizing a sample of twins in their early to mid-seventies, Swan and colleagues (1999) subjected data from the first edition of the California Verbal Learning Test (CVLT) to a phenotypic principal components analysis, and subsequently determined the heritability of the resulting factor scores Measures of learning and delayed recall loaded strongly onto the same factor, labeled as verbal learning and recall, the heritability of which was determined to be 56 (Swan et al, 1999) These results suggest a common source of genetic influences between learning and delayed recall; however, by examining the heritability of a predefined factor, the authors were not able determine whether unique genetic influences were present for the underlying measures Factors that are defined at the phenotypic level through the examination of standard covariance estimates typically account for only a portion of the overall variance in the variables of interest The residual variance for these variables is far from irrelevant, and can be used in multivariate twin analyses to identify variable-specific genetic and environmental influences that are crucial for distinguishing between measures that are highly correlated at the phenotypic level Multivariate twin methods make it possible to examine what is going on “beneath” the phenotypic level and are, thus, a powerful approach that may be able to shed new light on these episodic memory components In the present study, we utilized multivariate twin analyses in order to elucidate the genetic and environmental relationships between learning and delayed recall on the second edition of the California Verbal Learning Test (CVLT-2) (Delis, Kramer, Kaplan, & Ober, 2000) Learning was defined as the total number of words recalled across the five initial learning trials of the test, while delayed recall was examined in terms of performance on both short- and long-delay free recall conditions We hypothesized that based on the role of retrieval processes in each of these measures, as well as previous evidence of robust phenotypic correlations, a significant degree of genetic overlap would exist between our measures of learning and delayed recall Furthermore, we made three predictions regarding the possible presence of unique genetic influences If all components of episodic memory are influences by a single, global source of genetic influences, then model testing would indicate the presence of no variable-specific genetic influences If there are some genetic influences that are specific for acquisition and retrieval, then model testing would result in residual genetic influences for the learning trials versus short- and long- delay recall If there are some specific genetic influences as a function delay interval, then model testing would indicate residual genetic influences on each of the three memory measures

A test for common genetic and environmental vulnerability to depression and diabetes.

Abstract: Molecular genetic research has provided some evidence for the association between depression and metabolic disorders. We sought to determine if molecular findings are reflected in twin analyses testing if common genetic and environmental risk factors contribute to the co-occurrence of diabetes and depression. Data to derive depression and diabetes were collected from 1,237 male-male twins who participated in the 2005 Vietnam Era Twin Study of Aging (VETSA). The 1,237 twins were comprised of 347 MZ pairs, 3 MZ singletons, 267 DZ pairs and 6 unpaired twins. Depression was defined as a score below 46 on the Short Form-36 mental component summary score. Diabetes was defined by self report, use of anti-diabetic medications and insulin. Twin models were fit to estimate the correlation of genetic and environmental contributions to depression and diabetes. Consistent with other studies these data support the association between depression and diabetes (OR = 1.7; 95%CI: 1.1-2.7). Genetic vulnerability accounted for 50% (95%CI: 32%-65%) of the variance in risk for depression and 69% (95%CI: 52%-81%) of the variance in risk for diabetes. The genetic correlation between depression and diabetes was r = 0.19 (95%CI: 0-0.46) and the non-shared environmental correlation was r = 0.09 (95% CI: 0-0.45). Overall there is little evidence that common genetic and environmental factors account for the co-occurrence of depression and diabetes in middle aged men. Further research in female twins and larger cohorts is warranted.

Genetic architecture of context processing in late middle age: more than one underlying mechanism.

Abstract: Studies comparing young and older adults suggest a deficit in processing context information as a key mechanism underlying cognitive aging. However, the genetic architecture of context processing has not been examined. Consistent with previous results, we found evidence of functionally dissociable components of context processing accuracy in 1127 late middle-aged twins ages 51-60. One component emphasizes use of context cues to prepare responses (proactive cognitive control), and the other emphasizes adjustment of responses after probes are presented (reactive control). Approximately one-quarter of the variance in each component was accounted for by genes. Multivariate twin analysis indicated that genetic factors underlying two important components of context processing were independent of one another, thus implicating more than one underlying mechanism. Slower reaction time (RT) on noncontext processing trials was positively correlated with errors on the strongly proactive control component on which young adults outperform older adults, but RT was negatively correlated with errors on the strongly reactive control component on which older adults perform better. Although this RT measure was uncorrelated with chronological age in our age-homogeneous sample, slower RT was associated with performance patterns that were more like older adults. However, this did not generalize to other processing speed measures. Genetic correlations, which reflect shared genetic variance, paralleled the phenotypic correlations. There was also a positive genetic correlation between general cognitive ability and accuracy on the proactive control component, but there were still mostly distinct genetic influences underlying these measures. In contrast, the reactive control component was unrelated to general cognitive ability.

Adult romantic attachment, negative emotionality, and depressive symptoms in middle aged men: a multivariate genetic analysis.

Abstract: Adult romantic attachment styles reflect ways of relating in close relationships and are associated with depression and negative emotionality. We estimated the extent to which dimensions of romantic attachment and negative emotionality share genetic or environmental risk factors in 1,237 middle-aged men in the Vietnam Era Twin Study of Aging (VETSA). A common genetic factor largely explained the covariance between attachment-related anxiety, attachment-related avoidance, depressive symptoms, and two measures of negative emotionality: Stress-Reaction (anxiety), and Alienation. Multivariate results supported genetic and environmental differences in attachment. Attachment-related anxiety and attachment-related avoidance were each influenced by additional genetic factors not shared with other measures; the genetic correlation between the attachment measure-specific genetic factors was 0.41, indicating some, but not complete overlap of genetic factors. Genetically informative longitudinal studies on attachment relationship dimensions can help to illuminate the role of relationship-based risk factors in healthy aging.

Evidence of overlapping genetic diathesis of panic attacks and gastrointestinal disorders in a sample of male twin pairs.

Abstract: We explored the comorbidity between panic attacks (PA), whose symptoms can include gastrointestinal discomfort, and gastrointestinal disorders (GD). Structural equation modeling was used to analyze data from 1,874 MZ and 1,498 DZ male-male twin pairs from the Vietnam Era Twin Registry. PA and GD were associated (relative risk for GD = 2). The percentage of liability due to genetic factors was estimated to be 37% for PA and 31% for GD. There was significant correlation between the genetic risk factors for PA and GD (estimated r = .55, 95% CI of 34% to 82%) and no evidence of correlation between the environmental causes of PA and GD. Therefore, PA and GD comorbidity can be explained by overlapping genetic factors and not overlapping environmental factors. Although these data cannot identify a biological pathway for such a shared liability, it suggests the presence of GD may be informative for genetic studies of panic.