Marleen H. M. de Moor

Testing causality in the association between regular exercise and symptoms of anxiety and depression.

CONTEXT In the population at large, regular exercise is associated with reduced anxious and depressive symptoms. Results of experimental studies in clinical populations suggest a causal effect of exercise on anxiety and depression, but it is unclear whether such a causal effect also drives the population association. We cannot exclude the major contribution of a third underlying factor influencing exercise behavior and symptoms of anxiety and depression. OBJECTIVE To test causal effects of exercise on anxious and depressive symptoms in a population-based sample. DESIGN Population-based longitudinal study (1991-2002) in a genetically informative sample of twin families. SETTING Causal effects of exercise were tested by bivariate genetic modeling of the association between exercise and symptoms of anxiety and depression, correlation of intrapair differences in these traits among genetically identical twins, and longitudinal modeling of changes in exercise behavior and anxious and depressive symptoms. PARTICIPANTS A total of 5952 twins from the Netherlands Twin Register, 1357 additional siblings, and 1249 parents. All participants were aged 18 to 50 years. MAIN OUTCOME MEASUREMENTS Survey data about leisure-time exercise (metabolic equivalent task hours per week based on type, frequency, and duration of exercise) and 4 scales of anxious and depressive symptoms (depression, anxiety, somatic anxiety, and neuroticism, plus a composite score). RESULTS Cross-sectional and longitudinal associations were small and were best explained by common genetic factors with opposite effects on exercise behavior and symptoms of anxiety and depression. In genetically identical twin pairs, the twin who exercised more did not display fewer anxious and depressive symptoms than the co-twin who exercised less. Longitudinal analyses showed that increases in exercise participation did not predict decreases in anxious and depressive symptoms. CONCLUSION Regular exercise is associated with reduced anxious and depressive symptoms in the population at large, but the association is not because of causal effects of exercise.

Regular exercise, subjective wellbeing, and internalizing problems in adolescence: causality or genetic pleiotropy?

This study tests in a genetically informative design whether exercise behavior causally influences subjective wellbeing (SWB) and internalizing problems (INT). If exercise causally influences SWB and INT, genetic and environmental factors influencing exercise behavior will also influence SWB and INT. Furthermore, within genetically identical (MZ) twin pairs, the twin who exercises more should also show higher levels of SWB and lower levels of INT, than the co-twin who exercises less, because genetic confounding is excluded. Data on these phenotypes were available in a sample of 6317 adolescent twins and 1180 non-twin-siblings. Most participants had longitudinal data with 2-year follow-up. Exercise behavior was cross-sectionally and longitudinally associated with fewer internalizing problems and increased SWB (correlations ranged from 0.12 to 0.16). Cross-sectional and longitudinal associations were mainly accounted for by genetic factors, whereas the contribution of environmental factors was negligible. Within MZ twin pairs, the twin who exercised more did not show fewer internalizing problems and increased SWB. This was found cross-sectionally and longitudinally. We conclude that exercise behavior is associated with fewer internalizing problems and higher levels of SWB. The association largely reflects the effects of common genetic factors on these traits.

The Adult Netherlands Twin Register: twenty-five years of survey and biological data collection.

Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene x environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.

A genomewide association study of nicotine and alcohol dependence in Australian and Dutch populations

Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10,000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10(-8)) for ND (rs964170 in ARHGAP10 on chromosome 4, p = 4.43 x 10(-8)) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10(-9)), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10(-9)) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10(-8))). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepresentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be required before the detailed causes of comorbidity between AD and ND are understood.

Genome-wide linkage scan for athlete status in 700 British female DZ twin pairs

Association studies, comparing elite athletes with sedentary controls, have reported a number of genes that may be related to athlete status. The present study reports the first genome wide linkage scan for athlete status. Subjects were 4488 adult female twins from the TwinsUK Adult Twin Registry (793 monozygotic [MZ] and 1000 dizygotic [DZ] complete twin pairs, and single twins). Athlete status was measured by asking the twins whether they had ever competed in sports and what was the highest level obtained. Twins who had competed at the county or national level were considered elite athletes. Using structural equation modeling in Mx, the heritability of athlete status was estimated at 66%. Seven hundred DZ twin pairs that were successfully genotyped for 1946 markers (736 microsatellites and 1210 SNPs) were included in the linkage analysis. Identical-by-descent probabilities were estimated in Merlin for a 1 cM grid, taking into account the linkage disequilibrium of correlated SNPs. The linkage scan was carried out in Mx using the [Formula: see text]-approach. Suggestive linkages were found on chromosomes 3q22-q24 and 4q31-q34. Both areas converge with findings from previous studies using exercise phenotypes. The peak on 3q22-q24 was found at the SLC9A9 gene. The region 4q31-q34 overlaps with the region for which suggestive linkages were found in two previous linkage studies for physical fitness (FABP2 gene; Bouchard et al., 2000) and physical activity (UCP1 gene; Simonen et al., 2003). Future association studies should further clarify the possible role of these genes in athlete status.

Genome-Wide Association Study of Exercise Behavior in Dutch and American Adults

INTRODUCTION The objective of this study was to identify genetic variants that are associated with adult leisure time exercise behavior using genome-wide association (GWA) in two independent samples. METHODS Exercise behavior was measured in 1644 unrelated Dutch and 978 unrelated American adults of European ancestry with detailed questions about type, frequency, and duration of exercise. Individuals were classified into regular exercisers or nonexercisers using a threshold of 4 MET·h (metabolic equivalents-hours per week). GWA analyses of ∼1.6 million observed and imputed Single Nucleotide Polymorphism (SNP) were conducted in both samples independently using logistic regression in SNPTEST, including sex, age, and body mass index as covariates. A meta-analysis of the results was performed using the weighted inverse variance method in METAL. RESULTS Thirty-seven novel SNPs in the PAPSS2 gene and in two intergenic regions on chromosomes 2q33.1 and 18p11.32 were associated with exercise participation (pooled P values <1.0 × 10(-5)). Previously reported associations (ACE, CASR, CYP19A1, DRD2, LEPR, and MC4R genes) or linkage findings (2p22.3, 4q28, 4q31.21 7p13, 9q31, 11p15, 13q22, 15q13, 18q12.2, 18q21.1, 19p13.3, and 20q12) were not replicated, although suggestive evidence was found for association to rs12405556 in the LEPR gene (pooled P value 9.7 × 10(-4); American sample, P value 9.8 × 10(-5)) and for association to rs8036270 in the GABRG3 gene (pooled P value 4.6 × 10(-5)) in the linkage region 15q12-13. CONCLUSIONS The heritability of leisure time exercise behavior is likely to be accounted for by many genetic variants with small effect size. These can be detected by GWA as was shown here for the PAPSS2 gene, but larger samples with genome-wide genotypes and high-quality exercise data are needed for further progress.

Sex Differences in Genetic Architecture of Complex Phenotypes

We examined sex differences in familial resemblance for a broad range of behavioral, psychiatric and health related phenotypes (122 complex traits) in children and adults. There is a renewed interest in the importance of genotype by sex interaction in, for example, genome-wide association (GWA) studies of complex phenotypes. If different genes play a role across sex, GWA studies should consider the effect of genetic variants separately in men and women, which affects statistical power. Twin and family studies offer an opportunity to compare resemblance between opposite-sex family members to the resemblance between same-sex relatives, thereby presenting a test of quantitative and qualitative sex differences in the genetic architecture of complex traits. We analyzed data on lifestyle, personality, psychiatric disorder, health, growth, development and metabolic traits in dizygotic (DZ) same-sex and opposite-sex twins, as these siblings are perfectly matched for age and prenatal exposures. Sample size varied from slightly over 300 subjects for measures of brain function such as EEG power to over 30,000 subjects for childhood psychopathology and birth weight. For most phenotypes, sample sizes were large, with an average sample size of 9027 individuals. By testing whether the resemblance in DZ opposite-sex pairs is the same as in DZ same-sex pairs, we obtain evidence for genetic qualitative sex-differences in the genetic architecture of complex traits for 4% of phenotypes. We conclude that for most traits that were examined, the current evidence is that same the genes are operating in men and women.

Assessment of borderline personality features in population samples: Is the Personality Assessment Inventory-Borderline Features scale measurement invariant across sex and age?

Borderline personality disorder (BPD) is more often diagnosed in women than in men, and symptoms tend to decline with age. Using a large community sample, the authors investigated whether sex and age differences in four main features of BPD, measured with the Personality Assessment Inventory-Borderline Features scale (PAI-BOR; Morey, 1991), are a result of measurement bias or if they represent true differences. The PAI-BOR was completed by four Sex x Age groups (N = 6,838). Multigroup confirmatory factor analysis showed that the PAI-BOR is measurement invariant across sex and age. Compared with men, women reported more borderline characteristics for affective instability, identity problems, and negative relationships but not for self-harm. Younger men had higher scores for identity problems and self-harm than did older men. Younger women had higher scores for identity problems and affective instability than did older women. Results suggest that the PAI-BOR can be used to study the etiology of BPD features in population-based samples and to screen for BPD features in clinical settings in both men and women of varying ages. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Genome-wide linkage scan for exercise participation in Dutch sibling pairs

This study was aimed at identifying the genomic loci linked to exercise participation in males and females. Cross-sectional exercise data of twins and siblings (18–50 years) were used from the Netherlands Twin Registry. The sample consisted of 1432 genotyped sibling pairs from 622 families (1120 sibling pairs were genotyped on all chromosomes). Exercise participation (no/yes, based on a cutoff criterion of four metabolic equivalents and 60 min weekly) was assessed by survey. Genotyping was based on 361 markers and an average marker density of 10.6 cM. Identical by descent status was estimated for a 1 cM grid. A variance components-based sex-limited linkage scan was carried out for exercise participation. The heritability of exercise participation in males was 68.5% and in females 46.3%. The genetic overlap was estimated at 0.32, indicating that partly different genes affect exercise in the two sexes. Suggestive linkage was found in all subjects on chromosome 19p13.3 (LOD=2.18). Although sex differences in linkage effect were not significant, mainly females contributed to the suggestive linkage. The 19p13.3–13.2 region harbors a number of genes related to muscle performance and muscle blood flow, which might affect exercise behavior through exercise ability. Most likely, a large number of genes with each small effects affect exercise participation in males and females. Large collaborative samples are needed to detect these effects.

Variance Components Models for Physical Activity With Age as Modifier: A Comparative Twin Study in Seven Countries

Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts.