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1.  A population-based twin study of functional somatic syndromes 
Psychological medicine  2008;39(3):497-505.
Background
The mechanisms underlying the co-occurrence of the functional somatic syndromes are largely unknown. No empirical study has explicitly examined how genetic and environmental factors influence the comorbidity of these syndromes. We aimed to examine how the comorbidity of functional somatic syndromes is influenced by genetic and environmental factors that are in common to the syndromes.
Methods
A total of 31,318 twins in the Swedish Twin Registry aged 41–64 underwent screening interviews via a computer-assisted telephone system from 1998 to 2002. Four functional somatic syndromes (chronic widespread pain, chronic fatigue, irritable bowel syndrome, and recurrent headache) and 2 psychiatric disorders (major depression and generalized anxiety disorder) were assessed using structured questions based on standard criteria for each illness in a blinded manner.
Results
Multivariate twin analyses revealed that a common pathway model with 2 latent traits that were shared by the 6 illnesses fit best to the women's data. One of the 2 latent traits loaded heavily on the psychiatric disorders, whereas the other trait loaded on all 4 of the functional somatic syndromes, particularly chronic widespread pain, but not on the psychiatric disorders. All illnesses except the psychiatric disorders were also affected by genetic influences that were specific to each.
Conclusions
The co-occurrence of functional somatic syndromes in women can be best explained by affective and sensory components in common to all these syndromes, as well as by unique influences specific to each of them. The findings clearly suggest a complex view of the multifactorial pathogenesis of these illnesses.
doi:10.1017/S0033291708003784
PMCID: PMC3947533  PMID: 18578896
2.  Initial Reactions to Tobacco Use and Risk of Future Regular Use 
Nicotine & Tobacco Research  2012;15(2):509-517.
Introduction: Studies suggest that initial smoking pleasure influences future smoking behavior. We investigated how initial reactions to cigarettes or Swedish smokeless tobacco (snus) were associated with future use among 10,708 adults from the Swedish Twin Registry.
Methods: The Early Smoking Experience questionnaire captured physiologic reactions to initial tobacco use. Binary recursive partitioning (BRP) identified combinations of initial reactions predictive of regular tobacco use. Analyses, stratified by sex, were conducted separately among those who experimented with only cigarettes (EC), only snus (ES), and both products (EC+S).
Results: Among EC, 39.8% of men and 43.7% of women became smokers, while among ES, 78.6% of men and 53.7% of women became snus users. Among EC+S, 31.3% of men and 20.0% of women became dual users. BRP identified different reactions as predictive of future smoking for men (buzz) and women (dizziness, difficulty inhaling). No initial reaction predicted future snus use among men, but pleasant sensations, later age at first use, and relaxation predicted future snus use for women. Among EC+S, future exclusive use of either product was associated with a favorable initial reaction to that product. Dual users experienced higher prevalence of pleasant reactions and lower prevalence of unpleasant reactions in response to both products.
Conclusions: Our findings support that those who progress to regular tobacco use may be sensitive to the rewarding effects of nicotine but suggest that initial reactions differ by tobacco type. A high proportion of men became regular snus users regardless of initial reactions.
doi:10.1093/ntr/nts180
PMCID: PMC3612000  PMID: 22949572
3.  Study of Dementia in Swedish Twins 
The Study of Dementia in Swedish Twins is a study of dementia in a defined population of twins. The goals included estimating heritability of Alzheimer's disease and identifying risk and protective factors in twin pairs discordant for the disease. The data, including not only diagnoses and age of onset but also extensive information about potential environmental risk factors, are now archived as Study ICPSR 25963 at National Archive for Computerized Data on Aging, Inter-university Consortium for Political and Social Research, at the University of Michigan, and available for researchers to use. Up to the time of archiving, 215 cases of dementia have been identified from a base sample of 2394 individuals.
doi:10.1017/thg.2012.68
PMCID: PMC3860317  PMID: 23046613
twins; heritability; dementia; Alzheimer's disease; epidemiology
4.  Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies 
PLoS ONE  2013;8(12):e83101.
Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.
doi:10.1371/journal.pone.0083101
PMCID: PMC3858365  PMID: 24340086
5.  Post-Zygotic and Inter-Individual Structural Genetic Variation in a Presumptive Enhancer Element of the Locus between the IL10Rβ and IFNAR1 Genes 
PLoS ONE  2013;8(9):e67752.
Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in ∼24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10Rβ, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.
doi:10.1371/journal.pone.0067752
PMCID: PMC3762855  PMID: 24023707
6.  Both Odor Identification and ApoE-ε4 Contribute to Normative Cognitive Aging 
Psychology and aging  2011;26(4):872-883.
Research indicates that apoliprotein E (ApoE) plays a role in the development of Alzheimer’s disease (AD) and possibly in the cognitive decline associated with normative aging. More recently, researchers have shown that ApoE is expressed in olfactory brain structures, and a relationship among ApoE, AD, and olfactory function has been proposed. In the current analyses, we investigated the contribution of ApoE and odor identification in decline trajectories associated with normative cognitive aging in various domains, using longitudinal data on cognitive performance available from the Swedish Adoption/Twin Study of Aging. Data on both ApoE status and olfactory functioning were available from 455 individuals ranging in age from 50 to 88 years at the first measurement occasion. Odor identification was measured via a mailed survey. Cognitive performance was assessed in up to 5 waves of in-person testing covering a period of 16 years. Latent growth curve analyses incorporating odor identification and ApoE status indicated a main effect of odor identification on the performance level in three cognitive domains: verbal, memory, and speed. A main effect of ApoE on rates of decline after age 65 was found for verbal, spatial, and speed factors. The consistency of results across cognitive domains provides support for theories that posit central nervous system-wide origins of the olfaction-cognition-ApoE relationship; however, olfactory errors and APOE ε4 show unique and differential effects on cognitive trajectory features.
doi:10.1037/a0023371
PMCID: PMC3753815  PMID: 21517181
cognitive aging; ApoE; odor identification; longitudinal; latent growth curve model
7.  Pulmonary Function as a Cause of Cognitive Aging 
Psychological science  2012;23(9):1024-1032.
Human aging is associated with decline in cognitive and physical functioning. Although pulmonary function predicts long-term performance (up to 10 years) on measures of cognitive function, recent data suggest the opposite relationship: Cognitive decline predicts self-reported physical limitations. In the study reported here, we utilized dual-change-score models to determine the directional relationship between pulmonary and cognitive function. Our sample consisted of 832 participants (ages 50–85 years at baseline), who were assessed in up to seven waves of testing across 19 years as part of the longitudinal Swedish Adoption/Twin Study of Aging. Changes in pulmonary function led to subsequent changes in fluid cognitive function, specifically, in tasks reflecting psychomotor speed and spatial abilities. There was no evidence that declines in cognitive function led to subsequent declines in pulmonary function. Thus, these data indicate a directional relationship from decreased pulmonary function to decreased cognitive function, a finding that underscores the importance of maintaining pulmonary function to ensure cognitive performance.
doi:10.1177/0956797612439422
PMCID: PMC3752604  PMID: 22864997
pulmonary function; cognitive function; dual-change-score model; longitudinal model; cognitive ability; statistical analysis; aging; health
8.  Genetic and Environmental Variation in Lung Function Drives Subsequent Variation in Aging of Fluid Intelligence 
Behavior genetics  2013;43(4):274-285.
Longitudinal studies document an association of pulmonary function with cognitive function in middle-aged and older adults. Previous analyses have identified a genetic contribution to the relationship between pulmonary function with fluid intelligence. The goal of the current analysis was to apply the biometric dual change score model to consider the possibility of temporal dynamics underlying the genetic covariance between aging trajectories for pulmonary function and fluid intelligence. Longitudinal data from the Swedish Adoption/Twin Study of Aging were available from 808 twins ranging in age from 50 to 88 years at the first wave. Participants completed up to six assessments covering a 19-year period. Measures at each assessment included spatial and speed factors and pulmonary function. Model-fitting indicated that genetic variance for FEV1 was a leading indicator of variation in age changes for spatial and speed factors. Thus, these data indicate a genetic component to the directional relationship from decreased pulmonary function to decreased function of fluid intelligence.
doi:10.1007/s10519-013-9600-3
PMCID: PMC3753107  PMID: 23760789
Pulmonary function; Cognitive function; Dual-change-score model; Longitudinal twin data; Statistical analysis; Aging; Health
9.  Genetic Variance in Processing Speed Drives Variation in Aging of Spatial and Memory Abilities 
Developmental psychology  2009;45(3):820-834.
Previous analyses have identified a genetic contribution to the correlation between declines with age in processing speed and higher cognitive abilities. The goal of the current analysis was to apply the biometric dual change score model to consider the possibility of temporal dynamics underlying the genetic covariance between aging trajectories for processing speed and cognitive abilities. Longitudinal twin data from the Swedish Adoption/Twin Study of Aging, including up to 5 measurement occasions covering a 16-year period, were available from 806 participants ranging in age from 50 to 88 years at the 1st measurement wave. Factors were generated to tap 4 cognitive domains: verbal ability, spatial ability, memory, and processing speed. Model-fitting indicated that genetic variance for processing speed was a leading indicator of variation in age changes for spatial and memory ability, providing additional support for processing speed theories of cognitive aging.
doi:10.1037/a0015332
PMCID: PMC3742113  PMID: 19413434
cognitive aging; longitudinal twin study; behavioral genetics; temporal dynamics; speed–cognition relationship
10.  Body mass index across midlife and cognitive change in late life 
Background
High midlife body mass index (BMI) has been linked to a greater risk of dementia in late life, but few have studied the effect of BMI across midlife on cognitive abilities and cognitive change in a dementia free sample.
Methods
We investigated the association between body mass index (BMI), measured twice across midlife (mean age 40 and 61 years, respectively), and cognitive change in four domains across two decades in the Swedish Adoption/Twin Study of Aging (SATSA).
Results
Latent growth curve models fitted to data from 657 non-demented participants showed that persons who were overweight/obese in early midlife had significantly lower cognitive performance across domains in late life and significantly steeper decline in perceptual speed, adjusting for cardio-metabolic factors. Both underweight and overweight/obesity in late midlife were associated with lower cognitive abilities in late life. However, the association between underweight and low cognitive abilities did not remain significant when weight decline between early and late midlife was controlled for.
Conclusions
There is a negative effect on cognitive abilities later in life related to being overweight/obese across midlife. Moreover, weight decline across midlife rather than low weight in late midlife per se was associated with low cognitive abilities. Weight patterns across midlife may be prodromal markers of late life cognitive health.
doi:10.1038/ijo.2012.37
PMCID: PMC3387354  PMID: 22450854
Aging; Body Mass Index; Cognition; Cognitive aging; Cognitive decline; Overweight; Obesity; Trajectories; Underweight; Weight changes
11.  IGEMS: The Consortium on Interplay of Genes and Environment across Multiple Studies 
The Interplay of Genes and Environment across Multiple Studies (IGEMS) group is a consortium of eight longitudinal twin studies established to explore the nature of social context effects and gene-environment interplay in late-life functioning. The resulting analysis of the combined data from over 17,500 participants aged 25–102 at baseline (including nearly 2,600 monogygotic and 4,300 dizygotic twin pairs and over 1,700 family members) aims to understand why early life adversity, and social factors such as isolation and loneliness, are associated with diverse outcomes including mortality, physical functioning (health, functional ability), and psychological functioning (well-being, cognition), particularly in later life.
doi:10.1017/thg.2012.110
PMCID: PMC3699700  PMID: 23186995
twins; gene-environment interaction; aging; longitudinal
12.  Sleep Problems are Associated with Binge Eating in Women 
Objective
We examined the association among current self-reported sleep problems, lifetime binge eating, and current obesity in women from the Swedish Twin study of Adults: Genes and Environment study
Method
Logistic regression analyses were used to evaluate these associations in 3,790 women aged 20-47 years.
Results
Binge eating was reported by 244 (6.4%) women and was positively associated with not getting enough sleep (p < .015), sleeping poorly (p < .001), problems falling asleep (p < .001), feeling sleepy during work or free time (p < .001), and disturbed sleep (p < .001). These same sleep variables, as well as napping and being a night person, were also significantly associated with obesity. The associations between binge eating and sleep remained after accounting for obesity.
Discussion
This investigation offers empirical support for an independent association between sleep problems and binge eating, which is likely due to complex psychological, biological, neuroendocrine, and metabolic factors.
doi:10.1002/eat.22003
PMCID: PMC3357460  PMID: 22331832
13.  Effects of Reducing the Frequency and Duration Criteria for Binge Eating on Lifetime Prevalence of Bulimia Nervosa and Binge Eating Disorder: Implications for DSM-5 
Objective
We assessed the impact of reducing the binge eating frequency and duration thresholds on the diagnostic criteria for bulimia nervosa (BN) and binge eating disorder (BED).
Method
We estimated the lifetime population prevalence of BN and BED in 13,295 female twins from the Swedish Twin study of Adults: Genes and Environment employing a range of frequency and duration thresholds. External validation (risk to co-twin) was used to investigate empirical evidence for an optimal binge eating frequency threshold.
Results
The lifetime prevalence estimates of BN and BED increased linearly as the frequency criterion decreased. As the required duration increased, the prevalence of BED decreased slightly. Discontinuity in co-twin risk was observed in BN between at least four times per month and at least five times per month. This model could not be fit for BED.
Discussion
The proposed changes to the DSM-5 binge eating frequency and duration criteria would allow for better detection of binge eating pathology without resulting in a markedly higher lifetime prevalence of BN or BED.
doi:10.1002/eat.20955
PMCID: PMC3235235  PMID: 21882218
14.  Accuracy and Sensitivity of Parkinsonian Disorder Diagnoses in Two Swedish National Health Registers 
Neuroepidemiology  2012;38(3):186-193.
Background
Swedish population-based national health registers are widely used data sources in epidemiological research. Register-based diagnoses of Parkinson's disease have not been validated against clinical information.
Methods
Parkinson's disease (PD) and other parkinsonian disorder diagnoses were ascertained in two registers, i.e. the National Patient Register (NPR) and the Cause of Death Register (CDR). Diagnoses were validated in terms of accuracy (positive predictive value) and sensitivity against data from a population-based study of PD in 1998–2004 that screened more than 35,000 persons and identified 194 cases of parkinsonian disorders including 132 PD cases (the gold standard for the purposes of this study).
Results
Accuracy for any parkinsonian disorder diagnoses was 88.0% in the NPR and 94.4% in the CDR. Accuracy of PD diagnoses was 70.8% in the NPR and 66.7% in the CDR. Misclassification between differential parkinsonian diagnoses was common. The accuracy of PD diagnoses in the NPR improved to 83.0% by restricting the definition to primary diagnoses only. The sensitivity of PD diagnoses in the NPR and CDR combined was 83.1%, with a mean time to detection of 6.9 years.
Conclusions
Population-based national health registers are valid data sources in epidemiological studies of PD or parkinsonian disorder etiology but are less suitable in studies of incidence or prevalence.
doi:10.1159/000336356
PMCID: PMC3375128  PMID: 22472568
Epidemiological methods; Parkinson disease; Parkinsonian disorders; Registries; Validation studies
15.  Genetic and Environmental Influences on Mothering of Adolescents: A Comparison of Two Samples 
Developmental psychology  2004;40(3):335-351.
This study examined 2 samples of adolescents and mothers using a child-based design (Nonshared Environment in Adolescent Development [NEAD] project, N = 395 families) and a parent-based design (Twin Moms [TM] project, N = 236 twin family pairs) to compare genetic and environmental influences on mothering. For both samples, the same measures of positivity, negativity, control, and monitoring were used. The use of matched child-based and parent-based samples enabled passive and nonpassive genotype–environment (GE) correlations to be approximated, providing information about process. Passive GE correlations were suggested for mother’s positivity and monitoring. For mother’s negativity and control, primarily nonpassive GE correlations were suggested. In several cases, both types of GE correlation were indicated. Finally, observer ratings of negativity and monitoring were influenced only by environmental factors.
doi:10.1037/0012-1649.40.3.335
PMCID: PMC1226934  PMID: 15122961
16.  Genetic Variants from Lipid-Related Pathways and Risk for Incident Myocardial Infarction 
PLoS ONE  2013;8(3):e60454.
Background
Circulating lipids levels, as well as several familial lipid metabolism disorders, are strongly associated with initiation and progression of atherosclerosis and incidence of myocardial infarction (MI).
Objectives
We hypothesized that genetic variants associated with circulating lipid levels would also be associated with MI incidence, and have tested this in three independent samples.
Setting and Subjects
Using age- and sex-adjusted additive genetic models, we analyzed 554 single nucleotide polymorphisms (SNPs) in 41 candidate gene regions proposed to be involved in lipid-related pathways potentially predisposing to incidence of MI in 2,602 participants of the Swedish Twin Register (STR; 57% women). All associations with nominal P<0.01 were further investigated in the Uppsala Longitudinal Study of Adult Men (ULSAM; N = 1,142).
Results
In the present study, we report associations of lipid-related SNPs with incident MI in two community-based longitudinal studies with in silico replication in a meta-analysis of genome-wide association studies. Overall, there were 9 SNPs in STR with nominal P-value <0.01 that were successfully genotyped in ULSAM. rs4149313 located in ABCA1 was associated with MI incidence in both longitudinal study samples with nominal significance (hazard ratio, 1.36 and 1.40; P-value, 0.004 and 0.015 in STR and ULSAM, respectively). In silico replication supported the association of rs4149313 with coronary artery disease in an independent meta-analysis including 173,975 individuals of European descent from the CARDIoGRAMplusC4D consortium (odds ratio, 1.03; P-value, 0.048).
Conclusions
rs4149313 is one of the few amino acid changing variants in ABCA1 known to associate with reduced cholesterol efflux. Our results are suggestive of a weak association between this variant and the development of atherosclerosis and MI.
doi:10.1371/journal.pone.0060454
PMCID: PMC3612051  PMID: 23555974
17.  Variation in the oxytocin receptor gene (OXTR) is associated with pair-bonding and social behavior 
Biological Psychiatry  2011;71(5):419-426.
Background
In specific vole and primate species the neuropeptide Oxytocin (OT) plays a central role in the regulation of pair-bonding behavior. Here we investigate to what extent genetic variants in the oxytocin receptor gene (OXTR) are associated with pair-bonding and related social behaviors in humans.
Methods
We first genotyped twelve Single Nucleotide Polymorphisms (SNPs) in the Twin and Offspring Study in Sweden (TOSS, N=2309) and the Swedish Twin Study of CHild and Adolescent Development (TCHAD, N=1240) comprising measures of self-reported pair-bonding behavior. In the TOSS-sample we further investigated one the SNPs for measures of marital status and quality. Moreover, in the TCHAD sample we explored the longitudinal relationship between precursors of pair-bonding during childhood and subsequent behavior in romantic relationships. Finally, in TCHAD and in the Child and Adolescent Twin Study of Sweden (CATSS, N=1771) the association between the same SNP and childhood behaviors was investigated.
Results
One SNP (rs7632287) in OXTR was associated with traits reflecting pair-bonding in women in the TOSS and TCHAD samples. In girls the rs7632287 SNP was further associated with childhood social problems, which longitudinally predicted pair-bonding behavior in the TCHAD-sample. This association was replicated in the CATSS-sample in which an association between the same SNP and social interaction deficit symptoms from the autism spectrum was detected.
Conclusion
These results suggest an association between variation in OXTR and human pair-bonding and other social behaviors, possibly indicating that the well described influence of OT on affiliative behavior in voles could also be of importance for humans.
doi:10.1016/j.biopsych.2011.09.002
PMCID: PMC3266986  PMID: 22015110
Monogamy; Neuropeptide; Polymorphism; Autism; Affiliative behavior; Social Problems
18.  Genome-wide and gene-based association implicates FRMD6 in Alzheimer disease 
Human Mutation  2012;33(3):521-529.
Genome-wide association studies (GWAS) that allow for allelic heterogeneity may facilitate the discovery of novel genes not detectable by models that require replication of a single variant site. One strategy to accomplish this is to focus on genes rather than markers as units of association, and so potentially capture a spectrum of causal alleles that differ across populations. Here, we conducted a GWAS of Alzheimer disease (AD) in 2586 Swedes and performed gene-based meta-analysis with three additional studies from France, Canada, and the United States, in total encompassing 4259 cases and 8284 controls. Implementing a newly designed gene-based algorithm, we identified two loci apart from the region around APOE that achieved study-wide significance in combined samples, the strongest finding being for FRMD6 on chromosome 14q (p = 2.6 × 10−14) and a weaker signal for NARS2 that is immediately adjacent to GAB2 on chromosome 11q (p = 7.8 × 10−9). Ontology-based pathway analyses revealed significant enrichment of genes involved in glycosylation. Results suggest that gene-based approaches that accommodate allelic heterogeneity in GWAS can provide a complementary avenue for gene discovery and may help to explain a portion of the missing heritability not detectable with SNPs derived from marker-specific meta-analysis.
doi:10.1002/humu.22009
PMCID: PMC3326347  PMID: 22190428
Alzheimer; GWAS; association; gene-based; FRMD6; GAB2
19.  Pleiotropy in the presence of allelic heterogeneity: alternative genetic models for the influence of APOE on serum LDL, CSF Aβ42, and Dementia 
The two genetic polymorphisms, rs7412 and rs429358, that collectively form the ε2, ε3, and ε4 alleles of apolipoprotein E (APOE)are among the most widely studied sequence variants in the genome. The predominant model for testing APOE involves the haplotype combinations of ε2, ε3, and ε4 and has been basis of associations with dementia, atherosclerosis, and serum lipid levels. Here, we demonstrate the functional independence of these two component sites, with rs7412 contributing to the majority of variance in serum LDL (p = 10−20), whereas rs429358 alone influences variance in CSF Aβ42(p = 10 −17). This latter relationship is also reflected in the association of APOE with dementia, where rs429358 strongly influences disease (p = 10−67), but rs7412 does not. Models based upon ε2, ε3, and ε4 explained less variance for both dementia risk and CSF Aβ42 than did rs429358 alone. When adjusted for CSF Aβ42, the association of rs429358 with dementia is greatly reduced but remains significant indicating that APOE polymorphism influences disease by additional mechanisms distinct from Aβ42 metabolism. We reach four principal conclusion from this study; 1) rs429358 alone is responsible for the association of APOE with dementia 2) The association of APOE with dementia is substantially mediated by its effect on CNS Aβ42 levels 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE.
doi:10.3233/JAD-2010-100864
PMCID: PMC3547982  PMID: 20847432
LDL; Alzheimer Disease; amyloid; association; CSF
20.  Work-Related Stress May Increase the Risk of Vascular Dementia 
OBJECTIVES
We examined job control, job demands, social support at work, and job strain (ratio of demands to control) in relation to risk of any dementia, Alzheimer’s disease (AD), and vascular dementia (VaD).
DESIGN
A cohort study.
SETTING
The population-based Study of Dementia in Swedish Twins.
PARTICIPANTS
A total of 257 dementia cases (167 AD, 46 VaD) and 9,849 non-demented individuals.
MEASUREMENTS
Dementia diagnoses were based on telephone screening for cognitive impairment followed by in-person clinical work-up. An established job exposure matrix was matched to main occupation categories to measure work characteristics.
RESULTS
In generalized estimating equations (adjusted for the inclusion of complete twin pairs), lower job control was associated with greater risk of any dementia (odds ratio [OR]=1.17, 95% confidence interval [95%CI] 1.04-1.31) and VaD specifically (OR=1.39, 95% CI 1.07-1.81). Lower social support at work was associated with increased risk of dementia (OR=1.15, 95% CI 1.03-1.28), AD (OR=1.14, 95% CI 1.00-1.31), and VaD (OR=1.28, 95% CI=1.02-1.60). Greater job strain was associated with increased risk of VaD only (OR=1.28, 95% CI 1.02-1.60), especially in combination with low social support (OR=1.35, 95% CI 1.11-1.64). Age, gender, education, and cardiovascular disease were controlled. Results were not explained by work complexity or manual work. No differences in work-related stress scores were observed in the 54 twin pairs discordant for dementia, although only two pairs included a twin with VaD.
CONCLUSION
Work-related stress including low job control and low social support at work may increase the risk of dementia, particularly VaD. Modification to work environment that includes attention to social context and provision of meaningful roles for the workers may contribute to the efforts to promote cognitive health.
doi:10.1111/j.1532-5415.2011.03777.x
PMCID: PMC3258308  PMID: 22175444
Work-related stress; job strain; dementia; vascular dementia
21.  Genetic and Environmental Influences on the Relationship between Flow Proneness, Locus of Control and Behavioral Inhibition 
PLoS ONE  2012;7(11):e47958.
Flow is a psychological state of high but subjectively effortless attention that typically occurs during active performance of challenging tasks and is accompanied by a sense of automaticity, high control, low self-awareness, and enjoyment. Flow proneness is associated with traits and behaviors related to low neuroticism such as emotional stability, conscientiousness, active coping, self-esteem and life satisfaction. Little is known about the genetic architecture of flow proneness, behavioral inhibition and locus of control – traits also associated with neuroticism – and their interrelation. Here, we hypothesized that individuals low in behavioral inhibition and with an internal locus of control would be more likely to experience flow and explored the genetic and environmental architecture of the relationship between the three variables. Behavioral inhibition and locus of control was measured in a large population sample of 3,375 full twin pairs and 4,527 single twins, about 26% of whom also scored the flow proneness questionnaire. Findings revealed significant but relatively low correlations between the three traits and moderate heritability estimates of .41, .45, and .30 for flow proneness, behavioral inhibition, and locus of control, respectively, with some indication of non-additive genetic influences. For behavioral inhibition we found significant sex differences in heritability, with females showing a higher estimate including significant non-additive genetic influences, while in males the entire heritability was due to additive genetic variance. We also found a mainly genetically mediated relationship between the three traits, suggesting that individuals who are genetically predisposed to experience flow, show less behavioral inhibition (less anxious) and feel that they are in control of their own destiny (internal locus of control). We discuss that some of the genes underlying this relationship may include those influencing the function of dopaminergic neural systems.
doi:10.1371/journal.pone.0047958
PMCID: PMC3487896  PMID: 23133606
22.  Occupational exposure in Parkinsonian disorders: A 43-year prospective cohort study in men 
Parkinsonism & related disorders  2011;17(9):677-682.
Background
Several occupations and occupational exposures have been investigated for associations with Parkinson’s disease. Common findings are increased risk associated with pesticide exposure and no association between Parkinson’s disease and welding.
Methods
We explored the association between a broad range of possible occupational risk factors and Parkinson’s disease as well as Parkinson’s disease plus other forms of parkinsonism (referred to as Parkinsonian disorders), using prospectively collected data in the population-based Swedish Twin Registry. A cohort of 14,169 Swedish men was followed for up to 43 years. We identified 234 Parkinsonian disorders cases including 204 Parkinson’s disease cases with complete data. We assessed exposure to 14 chemical and biological compounds through a job exposure matrix. Hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, smoking, and education were used to estimate the relative risk of disease associated with exposure.
Results
Exposure to inorganic dust was associated with increased risk of Parkinson’s disease and Parkinsonian disorders, HR 1.6 (95% CI 1.1–2.4) and 1.5 (1.0–2.2) respectively. There was no association between Parkinson’s disease or Parkinsonian disorders and occupational exposure to pesticides, welding smoke, metal dust, wood dust, animal handling, stone and concrete dust, chrome and nickel dust, quartz dust, organic dust, oil, asbestos, organic solvents and irritating gas.
Conclusions
Inorganic dust should be explored further as a potential risk factor for Parkinson’s disease. Occupational exposure to pesticides and twelve other compounds explored in this study may not be associated with risk of Parkinson’s disease in Swedish men.
doi:10.1016/j.parkreldis.2011.06.009
PMCID: PMC3200471  PMID: 21733735
Parkinson disease; Occupational exposure; Prospective studies
23.  A Population-Based Study of Gastroesophageal Reflux Disease and Sleep Problems in Elderly Twins 
PLoS ONE  2012;7(10):e48602.
Background & Aims
Previous studies indicate an association between sleep problems and gastroesophageal reflux disease (GERD). Although both these conditions separately have moderate heritabilities, confounding by genetic factors has not previously been taken into account. This study aimed to reveal the association between sleep problems and GERD, while adjusting for heredity and other potential confounding factors.
Methods
This cross-sectional population-based study included all 8,014 same-sexed twins of at least 65 years of age and born in Sweden between 1886 and 1958, who participated in telephone interviews in 1998–2002. Three logistic regression models were used 1) external control analysis, 2) within-pair co-twin analysis with dizygotic (DZ) twin pairs discordant for GERD, and 3) within-pair co-twin analysis with monozygotic (MZ) twin pairs discordant for GERD. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and adjusted for established risk factors for GERD, i.e. sex, age, body mass index (BMI), tobacco smoking, and educational level.
Results
A dose-response association was identified between increasing levels of sleep problems and GERD in the external control analysis. Individuals who often experienced sleep problems had a two-fold increased occurrence of GERD compared to those who seldom had sleep problems (OR 2.0, 95% CI 1.8–2.4). The corresponding association was of similar strength in the co-twin analysis including 356 DZ pairs (OR 2.2, 95% CI 1.6–3.4), and in the co-twin analysis including 210 MZ pairs (OR 1.5, 95% CI 0.9–2.7).
Conclusion
A dose-dependent association between sleep problems and GERD remains after taking heredity and other known risk factors for GERD into account.
doi:10.1371/journal.pone.0048602
PMCID: PMC3485348  PMID: 23119069
24.  Genetic Association of sequence variants near AGER/NOTCH4 and Dementia 
We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia cases and 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19–1.56, p = 1.36 × 10−6). Imputation of the associated genomic interval provided an improved signal at rs8365, near the 3'UTR of AGER (p = 7.34 × 10−7). The associated region extends 120kb encompassing 11 candidate genes. While AGER encodes a key receptor for β-amyloid protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (APP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.
doi:10.3233/JAD-2011-101848
PMCID: PMC3477600  PMID: 21297263
Dementia; NOTCH4; gene; association; inflammation
25.  The Impact of Environmental Experiences on Symptoms of Anxiety and Depression Across the Life Span 
Psychological Science  2011;22(10):1343-1352.
Symptoms of anxiety and depression are relatively stable over time. Can this stability be explained by genetic influences, or is it caused by the long-lasting effects of accumulating environmental experiences? To address this question, we analyzed longitudinally assessed symptoms of anxiety and depression in eight samples of monozygotic twins of widely varying ages. These samples were drawn from American and European population-based registries. Using hierarchical linear modeling, we examined individual differences and individual changes in the level of symptoms over time. This method enabled us to decompose the variance into the predictable variance shared by both members of each pair of twins, the differences between individuals within pairs, and the residual variance. We then modeled how these components of individual variation changed over time. Within pairs, the twins’ predicted levels of symptoms increasingly diverged from childhood until late adulthood, at which point the divergence ceased. By middle adulthood, environmental experiences contributed substantially to stable and predictable interindividual differences in levels of anxiety and depression.
doi:10.1177/0956797611417255
PMCID: PMC3297659  PMID: 21948854
anxiety; depression; adult development; behavior genetics; emotional development

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