Selected Publications from 2012 and 2011

Kremen, W.,  Panizzon, M., Xian, H., Barch, D., Franz, C., Grant, M., Toomey, R., Lyons, M. Genetic architecture of context processing in late middle age: More than one underlying mechanism. (in press, Psychology and Aging).

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.

Read the full article: Kremen in press


Kubarych, T., Prom-Wormley, E., Franz, C., Panizzon, M., Dale, A., Fischl, B., Eyler, L., Fennema-Notestine, C., Grant, M., Hauger, R., Hellhammer, D., Jak, A., Jernigan, T., Lupien, S., Lyons, M., Mendoza, S., Neale, M., Seidman, L., Tsuang, M., Kremen, W. A twin study of hippocampal volume, self-esteem and well-being in middle age. Genes, Brain and Behavior, 2012, 11(5), 539-544

Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults,we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10,P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72,P < 0.001) and between left and right hippocampal volume(0.72, P < 0.001). In multivariate genetic analyses,a two-factor additive genetic and unique environmental(AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other.

Read the full article: Kubarych 2012


Franz, C., Panizzon, M., Eaves, L., Thompson, W., Lyons, M., Tsuang, M.,  Glatt, S.,  Kremen, W. Genetic and environmental multidimensionality of well- and ill- being in middle aged twin men. Behavior Genetics, 2012, 42(4), 579-591.

The goals of the study were to determine the extent to which the underlying structure of different types of well-being was multidimensional and whether well- and ill-being were influenced by similar or different genetic and environmental factors. Participants were 1226 male twins ages 51–60, from the Vietnam Era Twin Study of Aging. Measures included: psychological well-being, Multidimensional Personality Questionnaire Well-Being scale(MPQWB), life satisfaction, self-esteem, and depressive symptoms. A two-orthogonal-factor common pathway model fit the data well. Psychological well-being and self-esteem loaded most strongly on Factor 1, which was highly heritable (h2 = .79). Life satisfaction loaded most strongly on Factor 2, which was only moderately heritable(h2 = .32). Only MPQWB had measure-specific genetic influences. Depressive symptoms loaded on both factors,and only depressive symptoms had measure-specific common environmental influences. All measures had specific unique environmental influences. Results indicate that well being is genetically and environmentally multidimensional and that ill-being has partial overlap with both latent factors.

Read the full article: Franz 2012


Chen, C-H, Gutierrez, E.D., Thompson, W., Panizzon, M., Jernigan, T., Eyler, L., Fennema-Notestine, C.,  Jak, A., Neale, M., Franz, C., Lyons, M., Grant, M., Fischl, B., Seidman, L., Tsuang, M., Kremen, W., Dale, A. Hierarchical genetic organization of human cortical surface area. Science, 2012, 335(6076), 1634-1636.

Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions;however, the divisions represented previously undescribed phenotypes different from conventional(non–genetically based) parcellation systems. The genetic organization of cortical area was hierarchical,modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.

Read the full article: Chen 2012


Panizzon, M.,  Fennema-Notestine, C., Kubarych, T., Chen, C-H., Eyler, L., Fischl, B., Franz, C., Grant, M., Hamza, S., Jak, A., Jernigan, T., Lyons, M., Neale, M., Prom-Wormley, E., Seidman, L., Tsuang, M. Wu, H. Xian, H., Dale, A., Kremen, W. . Genetic and environmental influences of white and gray matter signal contrast: A new phenotype for imaging genetics? NeuroImage, 2012, 60(3), 1686-1695.

The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal(WM/GM contrast) has been found to vary as a function of age and Alzheimer’s disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environment determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59 years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using Free Surfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (.50), and lowest in the cingulate cortex (.24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from−.11 to−.54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from −.16 to −.34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics.

Read the full article: Panizzon 2012


Vasilopoulos, T., Franz, C., Panizzon, M., Xian, H., Grant, M., Lyons, M., Toomey, R., Jacobson, K., Kremen, W.  Genetic architecture of the Delis-Kaplan Executive Function System Trail Making Test: Evidence for distinct genetic influences on executive function” Neuropsychology, 2012, 26(2), 238-250.

Objective: To examine how genes and environments contribute to relationships among Trail Making Test(TMT) conditions and the extent to which these conditions have unique genetic and environmental influences. Method: Participants included 1,237 middle-aged male twins from the Vietnam Era Twin Study of Aging. The Delis-Kaplan Executive Function System TMT included visual searching, number and letter sequencing, and set-shifting components. Results: Phenotypic correlations among TMT conditions ranged from 0.29 to 0.60, and genes accounted for the majority (58–84%) of each correlation. Overall heritability ranged from 0.34 to 0.62 across conditions. Phenotypic factor analysis suggested a single factor. In contrast, genetic models revealed a single common genetic factor but also unique genetic influences separate from the common factor. Genetic variance (i.e., heritability) of number and letter sequencing was completely explained by the common genetic factor while unique genetic influences separate from the common factor accounted for 57% and 21% of the heritabilities of visual search and set shifting, respectively. After accounting for general cognitive ability, unique genetic influences accounted for 64% and 31% of those heritabilities. Conclusion: A common genetic factor, most likely representing a combination of speed and sequencing, accounted for most of the correlation among TMT 1–4. Distinct genetic factors, however, accounted for a portion of variance in visual scanning and set shifting. Thus, although traditional phenotypic shared variance analysis techniques suggest only one general factor underlying different neuropsychological functions in nonpatient populations, examining the genetic underpinnings of cognitive processes with twin analysis can uncover more complex etiological processes.

Read the full article: Vasilopoulos 2012


Kremen, W. Koenen, K., Afari, N., Lyons, M.  Twin studies of posttraumatic stress disorder: Differentiating vulnerability factors from sequelae. Neuropharmacology, 2012, 62(2), 647-653.

Posttraumatic stress disorder (PTSD) is defined by one’s response to an environmental event. However,genetic factors are important in determining people’s response to that event, and even their likelihood of being exposed to particular traumatic events in the first place. Classical twin designs can decompose genetic and environmental sources of variance. Such studies are reviewed extensively elsewhere, and we cover them only briefly in this review. Instead, we focus primarily on the identical co-twin control design. This design makes it possible to resolve the “chicken egg” dilemma inherent in standard case control designs, namely, distinguishing risk from sequelae. Abnormalities that are present in both the twin with PTSD and the unaffected co-twin suggest pre-existing vulnerability indicators. These include smaller hippocampal volume, large cavum septum pellucidum, more neurological soft signs, lower general intellectual ability, and poorer performance in the specific cognitive abilities of executive function, attention, declarative memory, and processing of contextual cues. In contrast, abnormalities in a twin with PTSD that are not present in the identical co-twin suggest consequences of PTSD or trauma exposure. These include psychophysiological responding, higher resting anterior cingulate metabolism,event-related potential abnormalities associated with attentional processes, recall intrusions, and possibly some types of chronic pain. Most co-twin control studies of PTSD have been small and come from the same twin registry of middle-aged male veterans. Consequently, there is a great need for replication and extension of the findings, particularly in women and younger individuals. The creation of new twin registries would do much toward accomplishing this goal.

This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Read the full article: Kremen 2012


Vasilopoulos, T., Kremen, W., Kim, K., Panizzon, M., Stein, P., Xian, H., Grant, M., Lyons, M., Toomey, R., Eaves, L., Franz, C., Jacobson, K. Untreated hypertension decreases heritability of cognition in late middle age.  Behavior Genetics, 2012, 42(1), 107-120.

Hypertension is a risk factor for cognitive decline, but the mechanisms underlying the effects of hypertension on cognition, particularly in midlife, are unclear. We examined whether hypertension modifies genetic influences on individual differences in cognition.Nine cognitive domains and general cognitive ability were assessed in a sample of 1,237 male twins aged 51–60 who were divided into three blood pressure groups: non-hypertensive; medicated hypertensive; and unmedicated hypertensive. Heritability was significantly lower among unmedicated hypertensives compared to medicated hypertensives and non-hypertensives for visual-spatial ability(p = 0.013) and episodic memory (p = 0.004). There were no heritability differences between non-hypertensives and medicated hypertensives. In addition, there were no significant differences in mean level cognition across the three blood pressure groups. These results suggest that in middle-aged men, untreated hypertension suppresses normal genetic influences on individual differences in certain domains of cognition prior to the emergence of hypertension-related effects on cognitive performance. These results further suggest that antihypertensive medication may protect against or reverse this effect.

Read the full article: Vasilopoulos 2012b


Panizzon, M., Hauger, R., Eaves, L., Chen, C.H., Dale, A., Eyler, L., Fischl, B., Fennema-Notestine, C., Franz, C., Grant, M., Jacobson, K., Jak, A., Lyons, M., Mendoza, S., Neale, M., Prom-Wormley, E., Seidman, L., Tsuang, M., Xian, H., Kremen, W. Genetic influences on hippocampal volume differ as a function of testosterone level in middle-aged men.  NeuroImage, 2012, 59(2) 1123-1131.

The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55.8 years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. However, a significant moderating effect of testosterone on the genetic and environmental determinants of hippocampal volume was observed. Genetic influences on hippocampal volume increased substantially as a function of increasing testosterone level, while environmental influences either decreased or remained stable. These findings provide evidence for an apparent gene-by-hormone interaction on hippocampal volume. To the best of our knowledge, this is the first study to demonstrate that the heritability of a brain structure in adults may be modified by an endogenous biological factor.

Read the full article: Panizzon 2012b


Kremen, W.S., Panizzon, M.S., Neale, M.C, Fennema-Notestine, C., Prom-Wormley, E., Eyler, L.T., Stevens, A., Franz, C.E., Lyons, M.J., Grant, M.D., Jak, A.J., Jernigan, T.L., Xian, H., Fischl, B., Thermenos, H., Seidman, L.J., Tsuang, M.T., and Dale, A.M.  Heritability of brain ventricle size: Converging evidence from inconsistent results.  Neurobiology of Aging, 2012, 33(1), 1-8. PMID: 20363053

Twin studies generally show great consistency for the heritability of brain structures. Ironically, the lateral ventricles—perhaps the most reliably measured brain regions of interest—are the most inconsistent when it comes to estimating genetic influences on their volume. Heritability estimates in twin studies have ranged from zero to almost 0.80. Here we aggregate heritability estimates from extant twin studies, and we review and reinterpret some of the findings. Based on our revised estimates, we conclude that lateral ventricular volume is indeed heritable. The weighted average heritability of the revised estimates was 0.54. Although accumulated environmental insults might seem most logical as the predominant cause of age-related ventricular expansion, the data strongly suggest that genetic influences on lateral ventricular volume are increasing with age. Genetic influences accounted for 32–35% of the variance in lateral ventricular volume in childhood, but about 75% of the variance in late middle and older age. These conclusions have implications for the basic understanding of the genetic and environmental underpinnings of normative and pathological brain aging.

Read the full article: Kremen 2012b