Publications

Although the genetic determinants of personality have been intensively investigated especially since Cloninger proposed his psychobiological model of temperament and character, findings to date remain inconclusive and very few studies have addressed the topic in large population cohorts. In the current study we investigated one gene family in its entirety by addressing the role of all known dopamine receptor genes, DRD1-DRD5, on Cloninger's temperament traits in a Finnish population-based birth cohort. The study sample (n = 1,434) was ascertained from the Northern Finland Birth Cohort 1966 with over 5,000 study individuals tested at the age of 31 years. We utilized the genetic homogeneity and genealogical structure of this population to uncover putative effects of these genes on temperament traits at the population level. Our strategy utilizing a large birth cohort and its well established genealogical structure represents an optimal design for studying normally distributed traits. We also wished to provide a comprehensive view to one biologically relevant gene family instead of testing single candidate genes. We report evidence of association of several SNPs at the 5' end of dopamine receptor D2 (DRD2) with Novelty seeking (low) and Harm avoidance (high), and at the 3' end of DRD2 with Persistence. The strongest evidence of association emerged from females. Our study supports the involvement of the dopamine pathway in temperament traits, in particular underlining the role of DRD2 in Novelty seeking, Harm avoidance and Persistence.

We study the effect of a dimplelike geometric imperfection on the critical buckling load of spherical elastic shells under pressure loading. This investigation combines precision experiments, finite element modeling, and numerical solutions of a reduced shell theory, all of which are found to be in excellent quantitative agreement. In the experiments, the geometry and magnitude of the defect can be designed and precisely fabricated through a customizable rapid prototyping technique. Our primary focus is on predictively describing the imperfection sensitivity of the shell to provide a quantitative relation between its knockdown factor and the amplitude of the defect. In addition, we find that the buckling pressure becomes independent of the amplitude of the defect beyond a critical value. The level and onset of this plateau are quantified systematically and found to be affected by a single geometric parameter that depends on both the radius-to-thickness ratio of the shell and the angular width of the defect. To the best of our knowledge, this is the first time that experimental results on the knockdown factors of imperfect spherical shells have been accurately predicted, through both finite element modeling and shell theory solutions.

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

Emerging evidence indicates that variation in the transcription factor 7-like 2 (TCF7L2) gene may play a role in the pathogenesis of type 2 diabetes. In a prospective, nested, case-control study (n = 3,520) within the Nurses’ Health Study (687 type 2 diabetic case and 1,051 control subjects) and the Health Professionals Follow-up Study (886 case and 896 control subjects), we examined the association of a common variant of the TCF7L2 gene (rs12255372 [T/G]) with type 2 diabetes risk among Caucasians. Frequencies of the T-allele were significantly higher among case than control subjects; each copy of the T-allele was associated with a 1.32-fold (P = 0.0002) and 1.53-fold (P < 0.0001) increased type 2 diabetes risk in women and men, respectively. The odds ratios (95% CI) associated with homozygous carriers of the T-allele were 1.86 (1.30–2.67) and 2.15 (1.48–3.13) in women and men, respectively. Population-attributable risks for diabetes associated with the T-allele were 14.8 and 22.3% for women and men, respectively. In a meta-analysis of 3,347 case and 3,947 control sujects, each copy of the T-allele was associated with a 1.48-fold increased risk (P < 10−16). Our findings confirm that the TCF7L2 gene represents an important locus for predicting inherited susceptibility to type 2 diabetes.

This population-based follow-up study investigated the comorbidities, medication use, and healthcare services among women with polycystic ovary syndrome (PCOS) at age 46 years.

AbstractIt is becoming increasingly recognized that early-life nutritional, metabolicand environmental factors can have a long-term impact on the early onsetof obesity, type 2 diabetes and cardiovascular diseases. Numerous experi-mental and epidemiological observations support the concept that an indi-vidual’s response to their adult lifestyle and nutritional environmentdepends not only on their genetic susceptibility but also on their previousearly-life experiences. The current research challenge is to determine theprimary pathways contributing to ‘non- or epi-genetic’ causes of excessadult weight gain and adiposity. Evidence from the fields of genetic epide-miology, life course modelling and diet-induced foetal programming allsupport a role for the FTO gene in this complex biological interaction. Itmay provide a missing link in the developmental regulation of energymetabolism. Our review therefore considers the role of the FTO gene inthe early-life determination of body weight, body composition and energybalance. We will summarize current knowledge on FTO biology combin-ing human genetic epidemiology, molecular models and findings from ani-mal studies. Notably, we will focus on the role of FTO in energy balancein humans, the importance of FTO polymorphisms in childhood growthand the impact of foetal nutrition. Ultimately, we propose a new hypothe-sis for future research designed to understand the role of FTO in settinggene expression in metabolically active tissues.Keywords animal models, early life, foetal programming, FTO, geneticepidemiology, obesity.

Background— Adherence to several diet quality scores, including the Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension, has been associated with lower risk of cardiovascular disease (CVD), but little is known about how changes in these scores over time influence subsequent CVD risk. Methods and Results— We analyzed the association between 4-year changes in the 3 diet quality scores (Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension) and subsequent cardiovascular disease (CVD) risk among 29 343 men in the Health Professionals Follow-up Study and 51 195 women in the Nurses’ Health Study (1986–2010). During 1 394 702 person-years of follow-up, we documented 11 793 CVD cases. Compared with participants whose diet quality remained relatively stable in each 4-year period, those with the greatest improvement in diet quality scores had a 7% to 8% lower CVD risk in the subsequent 4-year period (pooled hazard ratio, 0.92 [95% confidence interval (CI), 0.87–0.99] for the Alternative Healthy Eating Index; 0.93 [95% CI, 0.85–1.02] for the Alternative Mediterranean Diet score; and 0.93 [95% CI, 0.87–0.99] for the Dietary Approach to Stop Hypertension; all P for trend <0.05). In the long term, increasing the diet scores from baseline to the first 4-year follow-up was associated with lower CVD risk during the next 20 years (7% [95% CI, 1–12] for the Alternative Healthy Eating Index, and 9% [95% CI, 3–14] for the Alternative Mediterranean Diet score). A decrease in diet quality scores was associated with significantly elevated risk of CVD in subsequent time periods. Conclusions— Improving adherence to diet quality scores over time is associated with significantly lower CVD risk in both the short term and long term.

The fabrication and properties of “fluoroalkylated paper” (“R F paper”) by vapor‐phase silanization of paper with fluoroalkyl trichlorosilanes is reported. R F paper is both hydrophobic and oleophobic: it repels water ( θ app H 2 O >140°), organic liquids with surface tensions as low as 28 mN m ‐1 , aqueous solutions containing ionic and non‐ionic surfactants, and complex liquids such as blood (which contains salts, surfactants, and biological material such as cells, proteins, and lipids). The propensity of the paper to resist wetting by liquids with a wide range of surface tensions correlates with the length and degree of fluorination of the organosilane (with a few exceptions in the case of methyl trichlorosilane‐treated paper), and with the roughness of the paper. R F paper maintains the high permeability to gases and mechanical flexibility of the untreated paper, and can be folded into functional shapes (e.g., microtiter plates and liquid‐filled gas sensors). When impregnated with a perfluorinated oil, R F paper forms a “slippery” surface (paper slippery liquid‐infused porous surface, or “paper SLIPS“) capable of repelling liquids with surface tensions as low as 15 mN m ‐1 . The foldability of the paper SLIPS allows the fabrication of channels and flow switches to guide the transport of liquid droplets.

This paper presents a study of the performance of the collocation and Galerkin methods using Hermite bi-cubic basis functions. It is a sequel to the studies of Houstis et al. [6] and Weiser et al. [15]. The two methods have the linear systems solved by direct methods, band Gauss elimination or Cholesky factorization. The problem domain consists of linear, self-adjoint elliptic equations on two-dimensional rectangular domains. The measures of performance are computer time and memory needed to achieve moderate accuracy. The earlier study comparing finite element and finite difference methods observes that collocation uses less computer time than Galerkin. The second study gave detailed operation counts which support this observation, but also gave substantial experimental evidence to the contrary. We use a new implementation of the collocation method by E. N. Houstis which is tailored for rectangular domains (the one used in Houstis et al. [6] was designed for general domains). We use the same Galerkin implementation that Weiser et al. used. We outline the process of comparing the performance of PDE software and discuss the difficulty of reaching definite conclusions. We analyze the question of error measurement and note that the example given in Weiser et al. [15] as a counterexample to the practice of measuring the error at the grid points or knots (as done in Houstis et al. [6]) is a singular problem and also a counterexample to the approach of measuring the error on a fixed set of points. This study strongly supports the hypothesis that (with these implementations of the methods) collocation performs better than Galerkin for computer time and versus error. We observe that a feature of the particular computing environment causes the Galerkin program to use twice as much memory as necessary and a “normal” implementation should be expected to use nearly the same memory as the collocation program.

Importance Strategies targeting body composition may help prevent chronic diseases in persons with excess weight, but randomized clinical trials evaluating lifestyle interventions have rarely reported effects on directly quantified body composition. Objective To evaluate the effects of a lifestyle weight-loss intervention on changes in overall and regional body composition. Design, Setting, and Participants The ongoing Prevención con Dieta Mediterránea-Plus (PREDIMED-Plus) randomized clinical trial is designed to test the effect of the intervention on cardiovascular disease prevention after 8 years of follow-up. The trial is being conducted in 23 Spanish research centers and includes men and women (age 55-75 years) with body mass index between 27 and 40 and metabolic syndrome. The trial reported herein is an interim subgroup analysis of the intermediate outcome body composition after 3-year follow-up, and data analysis was conducted from February 1 to November 30, 2022. Of 6874 total PREDIMED-Plus participants, a subsample of 1521 individuals, coming from centers with access to a dual energy x-ray absorptiometry device, underwent body composition measurements at 3 time points. Intervention Participants were randomly allocated to a multifactorial intervention based on an energy-reduced Mediterranean diet (MedDiet) and increased physical activity (PA) or to a control group based on usual care, with advice to follow an ad libitum MedDiet, but no physical activity promotion. Main Outcomes and Measures The outcomes (continuous) were 3-year changes in total fat and lean mass (expressed as percentages of body mass) and visceral fat (in grams), tested using multivariable linear mixed-effects models. Clinical relevance of changes in body components (dichotomous) was assessed based on 5% or more improvements in baseline values, using logistic regression. Main analyses were performed in the evaluable population (completers only) and in sensitivity analyses, multiple imputation was performed to include data of participants lost to follow-up (intention-to-treat analyses). Results A total of 1521 individuals were included (mean [SD] age, 65.3 [5.0] years; 52.1% men). In comparison with the control group (n=761), participants in the intervention arm (n=760) showed greater reductions in the percentage of total fat (between group differences after 1-year, −0.94% [95% CI, −1.19 to −0.69]; 3 years, −0.38% [95% CI, −0.64 to −0.12] and visceral fat storage after 1 year, -126 g [95% CI, −179 to −73.3 g]; 3 years, −70.4 g [95% CI, −126 to −15.2 g] and greater increases in the percentage of total lean mass at 1 year, 0.88% [95% CI, 0.63%-1.12%]; 3-years 0.34% [95% CI, 0.09%-0.60%]). The intervention group was more likely to show improvements of 5% or more in baseline body components (absolute risk reduction after 1 year, 13% for total fat mass, 11% for total lean mass, and 14% for visceral fat mass; after 3-years: 6% for total fat mass, 6% for total lean mass, and 8% for visceral fat mass). The number of participants needed to treat was between 12 and 17 to attain at least 1 individual with possibly clinically meaningful improvements in body composition. Conclusions and Relevance The findings of this trial suggest a weight-loss lifestyle intervention based on an energy-reduced MedDiet and physical activity significantly reduced total and visceral fat and attenuated age-related losses of lean mass in older adults with overweight or obesity and metabolic syndrome. Continued follow-up is warranted to confirm the long-term consequences of these changes on cardiovascular clinical end points. Trial Registration isrctn.org Identifier: ISRCTN89898870