Showing papers by "Carol E. Franz published in 2018"

Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts.

Abstract: BACKGROUND: Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. METHODS AND FINDINGS: The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. CONCLUSIONS: Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2.

Stability of genetic and environmental influences on executive functions in midlife.

Abstract: Research on executive functions (EFs) has revealed that individual differences in general EF abilities are highly correlated across the first few decades of life, especially at the level of genetic influences. Our work has also provided evidence for substantial heritability of this Common EF factor in midlife, but it remains unclear whether individual differences in Common EFs continue to show strong stability in middle age. We examined data from 1,464 middle-aged twins from the Vietnam Era Twin Study of Aging, most of whom completed 7 neuropsychological measures of EFs at 2 points in middle age (Mages = 56 and 62). Confirmatory factor analysis indicated that individual differences in Common EF, a latent factor explaining variation in seven neuropsychological EF tasks, were highly correlated across this 6-year period (r = .97), and that the same genetic and environmental influences were operating across this interval (genetic and shared environmental correlations = 1.0, nonshared environment correlation = .95). Similar phenotypic and genetic stability was observed for a Working Memory (WM)-Specific latent factor, which explained additional variance in working memory span tasks not captured by Common EF (r = .98, genetic correlation = 1.0, nonshared environmental correlation = .88). There was a large mean-level performance decline in Common EF (d = -.60) but not WM-Specific (d = -.03). These results suggest that there is substantial decline in Common EF abilities across middle age but that individual differences are almost perfectly stable. (PsycINFO Database Record

Mediators of the Effect of Childhood Socioeconomic Status on Late Midlife Cognitive Abilities: A Four Decade Longitudinal Study.

Abstract: Background and objectives Childhood socioeconomic status (cSES) is found to predict later-life cognitive abilities, yet the mechanisms underlying these associations remain unclear. The objective of this longitudinal study was to examine the direct and indirect paths through which cSES influences late midlife cognitive outcomes. Research design and methods Participants were 1,009 male twins in the Vietnam Era Twin Study of Aging (VETSA). At mean ages 20 and 62, participants completed a standardized test for general cognitive ability (GCA). The age 62 cognitive assessment also included in-person tests of processing speed, episodic memory, abstract reasoning, working memory, verbal fluency, visual-spatial ability, and executive functions. At mean age 56, participants were interviewed regarding their own and their parents' education and occupation, and completed questionnaires about cognitive leisure activities and sociodemographic information. Multiple mediation analyses were conducted to examine the direct path effects and indirect path effects of cSES through age 20 GCA, adult SES, and cognitive leisure activities on seven cognitive outcomes at age 62, adjusting for age, ethnicity, and non-independence of observations. Results Total (direct plus indirect) effects were significant for all measures with the exception of executive functions. Men from lower cSES backgrounds had poorer cognitive functioning in late midlife. The direct effect of cSES was partially mediated for abstract reasoning, and was fully mediated for the remaining six cognitive outcomes. Total indirect effects accounted for at least half of the total effects in each model, with paths through age 20 GCA explaining most of the total indirect effects. Discussion and implications cSES predicted cognitive functioning in late middle age Using multiple mediation models, we show that lower cSES predicts poorer cognition in late midlife primarily through young adult cognitive ability and to a lesser extent through SES in adulthood and engagement in cognitively stimulating activities.

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Abstract: Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Abstract: Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

Genetic and Environmental Influences on Verbal Fluency in Middle Age: A Longitudinal Twin Study.

Abstract: Mounting evidence suggests that measures of phonemic fluency and semantic fluency are differentially associated with other cognitive and health phenotypes, but few studies have examined their shared and unique variance, especially using genetically-informative designs. In this study, 1464 middle-aged twins completed six fluency subtests at up to two time-points (mean age 56 and 62 years). Confirmatory factor analyses supported a two-factor solution: a General Fluency latent factor explained variation in all six subtests and a Semantic-Specific factor accounted for additional variance in semantic subtests. Both factors were explained primarily by genetic influences at both waves (a2 = 0.57–0.76). There was considerable stability of individual differences over 6 years (r = .90 for General Fluency, r = .81 for Semantic-Specific), especially for genetic influences (rg = .94 and 1.0, respectively). These results suggest that semantic fluency can be viewed as a combination of general and semantic-specific variance, but phonemic fluency is captured entirely by the general factor.

Testing associations between cannabis use and subcortical volumes in two large population-based samples.

Abstract: Disentangling the putative impact of cannabis on brain morphology from other comorbid substance use is critical. After controlling for the effects of nicotine, alcohol and multi-substance use, this study aimed to determine whether frequent cannabis use is associated with significantly smaller subcortical grey matter volumes. Exploratory analyses using mixed linear models, one per region of interest (ROI), were performed whereby individual differences in volume (outcome) at seven subcortical ROIs were regressed onto cannabis and comorbid substance use (predictors). Two large population-based twin samples from the United States and Australia. 622 young Australian adults (66% female; μ = 25.9, SD=3.6), and 474 middle-age U.S. males (μ = 56.1 ) of predominately Anglo-Saxon ancestry with complete substance use and imaging data. Subjects with a history of stroke or traumatic brain injury were excluded. Magnetic resonance imaging (MRI) and volumetric segmentation methods were used to estimate volume in seven subcortical ROIs: thalamus; caudate nucleus; putamen; pallidum; hippocampus; amygdala; and nucleus accumbens. Substance use measurements included maximum nicotine and alcohol use, total lifetime multi-substance use, maximum cannabis use in the young adults, and regular cannabis use in the middle-age males. After correcting for multiple testing (p=0.007), cannabis use was unrelated to any subcortical ROI. However, maximum nicotine use was associated with significantly smaller thalamus volumes in middle-age males. In exploratory analyses based on young adult and middle age samples, normal variation in cannabis use is statistically unrelated to individual differences in brain morphology as measured by subcortical volume.

Brain structure mediates the association between height and cognitive ability.

Abstract: Height and general cognitive ability are positively associated, but the underlying mechanisms of this relationship are not well understood. Both height and general cognitive ability are positively associated with brain size. Still, the neural substrate of the height-cognitive ability association is unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to investigate whether the association between height and cognitive ability is mediated by cortical size. In addition to cortical volume, we used genetically, ontogenetically and phylogenetically distinct cortical metrics of total cortical surface area and mean cortical thickness. Height was positively associated with general cognitive ability and total cortical volume and cortical surface area, but not with mean cortical thickness. Mediation models indicated that the well-replicated height-general cognitive ability association is accounted for by individual differences in total cortical volume and cortical surface area (highly heritable metrics related to global brain size), and that the genetic association between cortical surface area and general cognitive ability underlies the phenotypic height-general cognitive ability relationship.

Association of Sleep Quality on Memory-Related Executive Functions in Middle Age.

Abstract: Objectives Sleep quality affects memory and executive function in older adults, but little is known about its effects in midlife. If it affects cognition in midlife, it may be a modifiable factor for later-life functioning. Methods We examined the association between sleep quality and cognition in 1220 middle-aged male twins (age 51-60 years) from the Vietnam Era Twin Study of Aging. We interviewed participants with the Pittsburgh Sleep Quality Index and tested them for episodic memory as well as executive functions of inhibitory and interference control, updating in working memory, and set shifting. Interference control was assessed during episodic memory, inhibitory control during working memory, and non-memory conditions and set shifting during working memory and non-memory conditions. Results After adjusting for covariates and correcting for multiple comparisons, sleep quality was positively associated with updating in working memory, set shifting in the context of working memory, and better visual-spatial (but not verbal) episodic memory, and at trend level, with interference control in the context of episodic memory. Conclusions Sleep quality was associated with visual-spatial recall and possible resistance to proactive/retroactive interference. It was also associated with updating in working memory and with set shifting, but only when working memory demands were relatively high. Thus, effects of sleep quality on midlife cognition appear to be at the intersection of executive function and memory processes. Subtle deficits in these age-susceptible cognitive functions may indicate increased risk for decline in cognitive abilities later in life that might be reduced by improved midlife sleep quality. (JINS, 2018, 24, 67-76).

Genetic relatedness of axial and radial diffusivity indices of cerebral white matter microstructure in late middle age

Abstract: Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD.

Longitudinal Twin Study of Subjective Health: Differences in Genetic and Environmental Components of Variance Across Age and Sex

Abstract: Objective The current analysis examines sex differences in longitudinal changes in genetic and environmental influences on three measures of subjective health (SH). Method Sample includes 7,372 twins (mean intake age = 73.22) with up to 8 waves of measurement (mean = 3.1). Three SH items were included: general self-rated health (SRH), health compared to age peers (COMP), and impact of health on activities (ACT) which previous research shows capture different frames of reference. Results Latent growth curve modeling indicated significant differences across gender and frame of reference in trajectories of change with age and in genetic and environmental contributions to change. Men have higher mean scores on all three SH measures, indicating better SH, but there were no sex differences in pattern of change with age. Accelerating declines with age were found for SRH and ACT, whereas COMP improved with age. Results indicated more genetic variance for women than men, but declining genetic variance for both after age 70. Increasing shared environmental variance with increasing age was also found for both sexes. Discussion As aging triggers a re-evaluation of the meaning of "good health," physical aspects of health may become less important and shared cultural conceptions of health may become more relevant. This change in conceptions of good health may reflect both aging and the change in composition of the elderly population as a result of selective survival.

Genetic risk for coronary heart disease alters the influence of Alzheimer's genetic risk on mild cognitive impairment

Abstract: Alzheimer's disease (AD) is under considerable genetic influence. We previously found that an AD polygenic risk score (PRS) was significantly associated with mild cognitive impairment (MCI), an early stage of AD. However, known susceptibility loci only explain a modest proportion of variance in MCI and AD outcomes. This small proportion could occur if the etiology of AD is heterogeneous. Poor cardiovascular health is also associated with increased risk for AD and has been found to interact with AD pathology. Conditions such as coronary artery disease (CAD) are also heritable, therefore we were interested in whether there are interactions between genetic risk for CAD and AD as there is phenotypically. A potential problem with this approach is that case-control designs based on prevalent cases of a disease with relatively high case-fatality rate (such as CAD) may be biased toward individuals who have long post-event survival times. Genome-wide association studies (GWAS) of prevalent cases may potentially identify protective risk loci. Therefore, we tested two CAD-PRSs: one based on a GWAS of incident cases and one on prevalent cases. As expected, the incidence-based CAD-PRS interacts with the AD-PRS to further increase MCI risk. Conversely, higher prevalence-based CAD-PRSs reduced the effect of AD genetic risk on MCI status. These results demonstrate: i) the utility of including multiple PRSs and their interaction effects; ii) how genetic risk for one disease may modify the impact of genetic risk for another; and iii) the importance of considering ascertainment procedures of GWAS being used for genetic risk prediction.

O2‐05‐03: bmi changes from normal to obese over four decades predict thinner cortices in regions related to alzheimer's and related dementia

Abstract: 1). In prospective analysis, the strength of association between vascular risk factor burden and brain volume became progressively stronger as vascular risk factors were measured progressively earlier in the lifespan (Figure 2). Findings were particularly strong in women. Conclusions:Vascular risk factors at younger ages and prolonged exposure among survivors appears to have detrimental effects on current and future brain volume, especially in women.