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.
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.
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.
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.
Monogamy; Neuropeptide; Polymorphism; Autism; Affiliative behavior; Social Problems
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.
Alzheimer; GWAS; association; gene-based; FRMD6; GAB2
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.
LDL; Alzheimer Disease; amyloid; association; CSF
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).
A cohort study.
The population-based Study of Dementia in Swedish Twins.
A total of 257 dementia cases (167 AD, 46 VaD) and 9,849 non-demented individuals.
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.
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.
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.
Work-related stress; job strain; dementia; vascular dementia
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.
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.
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.
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.
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.
Parkinson disease; Occupational exposure; Prospective studies
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.
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.
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).
A dose-dependent association between sleep problems and GERD remains after taking heredity and other known risk factors for GERD into account.
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.
Dementia; NOTCH4; gene; association; inflammation
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.
anxiety; depression; adult development; behavior genetics; emotional development
Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
serum lipids; polygenic; genome-wide association; polygenic score; pathway analysis
The relative importance of genetic and environmental factors for the occurrence of lower urinary tract symptoms (LUTS) is poorly understood.
To (1) estimate the prevalence of urinary incontinence (UI), overactive bladder (OAB), and other LUTS and (2) to assess the heritability of these symptoms.
Design, setting, and participants
Cross-sectional survey of LUTS in a national population-based cohort of Swedish twins 20–46 yr of age (n = 42 582) from the Swedish Twin Registry.
Prevalence rates were determined and heritability of LUTS (in female twins) was assessed using indicators of twin similarity.
Results and limitations
A total of 25 364 twins completed the questionnaire (response rate: 59.6%). LUTS were more common in women (UI: 7%; OAB: 9%; nocturia: 61%; micturition frequency: 18%) than in men (UI: 1%; OAB: 5%; nocturia: 40%; micturition frequency: 11%), and prevalence increased with age. The strongest genetic effects were observed for UI, frequency, and nocturia. The lowest estimate for genetic effects was observed for OAB where environmental effects dominated, and more specifically shared family environment accounted for a third or more of the total variation. For stress UI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Nonshared environmental effects were seen in the range of 45–65% for the various LUTS. The prevalence of LUTS was low in the men, and there were too few male cases to compute measures of similarity or heritability estimates.
This study provides robust evidence of a genetic influence for susceptibility to UI, frequency, and nocturia in women. In contrast, shared environmental factors seem more important for the predisposition to develop OAB, which may reflect familial patterns such as learning from parental behaviours.
To assess the influence of smoking, coffee and tea consumption on the risk for bladder pain syndrome (BPS) using the O'Leary Interstitial Cystitis Symptom Index (ICSI)
In 2005, all twins born 1959–1985 in Sweden (n = 42 852) were invited to participate in a web-based survey to screen for complex diseases including BPS. Analyses were limited to female twins with information regarding bladder pain symptoms (n = 9 349). Women with an ICSI score of 6 or greater with required nocturia and bladder pain were defined as having BPS symptoms. Logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Environmental and genetic influences were assessed in co-twin control analysis
Tea consumption was associated with an increased risk for BPS (OR 1.26, 95% CI 1.02–1.55 for low tea consumption; OR 1.74, 95% CI 1.24–2.44 for high tea consumption). Coffee consumption was not a risk factor for BPS (OR 1.1, 95% CI 0.84–1.45). Former, and current smoking, were both associated with a higher risk of BPS (OR 1.5, 95% CI 1.18–1.89; and OR 1.49, 95% CI 1.16–1.92 respectively) but results from co-twin control analysis suggested that the association between smoking and BPS was confounded by familial factors.
Tea and smoking are environmental risk factors for BPS which are amenable to intervention. The effects of smoking on the risk for BPS may, however, be confounded by familial factors
Bladder pain syndrome; Coffee; Smoking; Tea; Twins
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.
Practical limitations and sample size considerations often lead to broadening of diagnostic criteria for anorexia nervosa (AN) in research. The current study sought to elucidate the effects of this practice on resultant sample characteristics in terms of eating disorder behaviors, psychiatric comorbidities, temperament and personality characteristics, and heritability point estimates. Three definitions of AN were created: meeting all Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for AN (AN-DSM-IV), meeting all DSM-IV criteria except criterion D, amenorrhea, (AN-noD), and broadening DSM-IV AN criteria by allowing a higher body mass index value, eliminating criterion D, and allowing less stringent body weight concerns (AN-Broad). Using data from the Swedish Twin Registry, 473 women fit one of the three definitions of AN. Women with AN-DSM-IV reported significantly more eating disorder behaviors than women with AN-Broad. Women with AN-noD reported more comorbid psychiatric disorders than women with AN-DSM-IV and AN-Broad. Temperament and personality characteristics did not differ across the three groups. Heritability point estimates decreased as AN definition broadened. Broadening the diagnostic criteria for AN results in an increased number of individuals available for participation in research studies. However, broader criteria for AN yield a more heterogeneous sample with regard to eating disorder symptoms and psychiatric comorbidity than a sample defined by narrower criteria.
Anorexia Nervosa; Classification; Diagnostic Criteria; Eating Disorder
Large prospective cohort studies are critical for identifying etiologic factors for disease, but they require substantial long-term research investment. Such studies can be conducted as multisite consortia of academic medical centers, combinations of smaller ongoing studies, or a single large site such as a dominant regional health-care provider. Still another strategy relies upon centralized conduct of most or all aspects, recruiting through multiple temporary assessment centers. This is the approach used by a large-scale national resource in the United Kingdom known as the “UK Biobank,” which completed recruitment/examination of 503,000 participants between 2007 and 2010 within budget and ahead of schedule. A key lesson from UK Biobank and similar studies is that large studies are not simply small studies made large but, rather, require fundamentally different approaches in which “process” expertise is as important as scientific rigor. Embedding recruitment in a structure that facilitates outcome determination, utilizing comprehensive and flexible information technology, automating biospecimen processing, ensuring broad consent, and establishing essentially autonomous leadership with appropriate oversight are all critical to success. Whether and how these approaches may be transportable to the United States remain to be explored, but their success in studies such as UK Biobank makes a compelling case for such explorations to begin.
cohort studies; epidemiology; prospective studies
Inflammatory mechanisms have been implicated in Alzheimer’s disease (AD) and dementia. We therefore sought to study DNA sequence variation and serum levels of the potent inflammatory mediators Interleukin-6 (IL6) and C-reactive protein (CRP) in relation to AD and dementia.
Tagging single nucleotide polymorphisms (tagSNPs) were chosen to capture most variation in and around CRP and IL6 in 3937 elderly Swedish men and women (1,265 AD cases). A subset of the population (N=723) with serum measurements of CRP and IL6 was included in A) a nested case-control study of incident dementia cases, and B) a case-control study of prevalent dementia cases. None of the SNPs or haplotypes was significantly associated with AD or dementia after correcting for multiple testing nor were elevated baseline levels of hsCRP or IL6 (measured on average 4.3 years before dementia onset) significantly associated with risk of future AD or dementia. However, prevalent AD cases had higher levels of IL6 (measured on average 5.5 years after dementia onset) than age- and sex-matched controls, OR 2.24 (95% CI 1.27–3.95), p-value 0.006.
In summary, this data suggests that AD patients have an altered immune profile with higher circulating levels of IL6 than age-and sex-matched controls. However, neither variation in the CRP and IL6 genes nor circulating levels of their respective protein products were associated with an increased risk of developing late-life dementias.
Alzheimer disease; dementia; inflammation; interleukin-6; C-reactive protein; biological markers; candidate gene analysis; matched case-control studies; nested case-control studies
A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from ∼5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW–SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries.
common controls; genome-wide data; Nordic Control Database; population stratification
We examined the association between extremely low-frequency magnetic fields (EMF) and the risk of dementia and Alzheimer’s disease using all 9,508 individuals from the Study of Dementia in Swedish Twins (HARMONY) with valid occupational and diagnostic data.
Dementia diagnoses were based on telephone screening followed by in-person clinical workup. Main lifetime occupation was coded according to an established EMF exposure matrix. Covariates were age, gender, education, vascular risk factors, and complexity of work. Based on previous research, data were also analyzed separately for cases with disease onset by age 75 years versus later, men versus women, and those with manual versus nonmanual main occupation. We used generalized estimating equations with the entire sample (to adjust for the inclusion of complete twin pairs) and conditional logistic regression with complete twin pairs only.
Level of EMF exposure was not significantly associated with dementia or Alzheimer’s disease. However, in stratified analyses, medium and high levels of EMF exposure were associated with increased dementia risk compared with low level in cases with onset by age 75 years (odds ratio: 1.94, 95% confidence interval: 1.07–3.65 for medium, odds ratio: 2.01, 95% confidence interval: 1.10–3.65 for high) and in participants with manual occupations (odds ratio: 1.81, 95% confidence interval: 1.06–3.09 for medium, odds ratio: 1.75, 95% confidence interval: 1.00–3.05 for high). Results with 42 twin pairs discordant for dementia did not reach statistical significance.
Occupational EMF exposure appears relevant primarily to dementia with an earlier onset and among former manual workers.
Dementia; Magnetic fields; Occupation; Alzheimer’s disease
Background: self-reported body mass index (BMI) based on self-reported height and weight is a widely used measure of adiposity in epidemiological research. Knowledge about the accuracy of these measures in late life is scarce.
Objective: the study aimed to evaluate the accuracy and changes in accuracy of self-reported height, weight and BMI calculated from self-reported height and weight in late life.
Design: a longitudinal population-based study with five times of follow-up was conducted.
Participants: seven hundred seventy-four community-living men and women, aged 40–88 at baseline (mean age 63.9), included in The Swedish Adoption/Twin Study of Aging.
Methods: participants self-reported their height and weight in a questionnaire, and height and weight were measured by experienced research nurses at an in-person testing five times during a 20-year period. BMI was calculated as weight (kilogramme)/height (metre)2.
Results: latent growth curve modelling showed an increase in the mean difference between self-reported and measured values over time for height (0.038 cm/year) and BMI (0.016 kg/m2/year), but not for weight.
Conclusions: there is a very small increase in the mean difference between self-reported and measured BMI with ageing, which probably would not affect the results when self-reported BMI is used as a continuous variable in longitudinal studies.
body mass index; height; weight; reliability; elderly
To examine if the body mass index (BMI) in midlife is related to cognitive function 30 years later in a dementia-free sample.
BMI was reported in 1963 at age 50–60 years, and cognitive abilities were examined 30 years later in a longitudinal design with 5 measurement occasions at 2-year intervals (n = 417). The cognitive abilities examined included tests of long-term memory, short-term memory, speed, verbal and spatial ability.
Multilevel modeling adjusting for demographic and lifestyle factors, and relevant diseases showed that a higher BMI in midlife predicted lower test performance 30 years later. Significant associations between BMI and level of performance were found in all cognitive abilities; however, a higher midlife BMI was not associated with steeper cognitive decline.
Our results indicate that midlife overweight is related to lower overall cognitive function in old age. The fact that BMI-related effects were noted in mean-level cognitive performance, whereas only one ability showed differences in slopes, suggests that the negative effect of overweight has an onset before the entry into very old age.
Adiposity; Obesity; Cognition; Mental ability
We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P ∼ 10−72) followed by a previously reported association of ABCA1 (rs2230805 at P ∼ 10−8). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 × 10−6 for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r2 > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.
This study aimed to investigate empirically how and in what way individuals with symptoms of functional somatic syndromes should be classified. We also aimed to look into genetic and environmental influences on the classification.
A total of 28531 twins aged 41–64 underwent screening interviews via a computer-assisted data collection system from 1998 to 2002. Nine functional somatic symptoms (abnormal tiredness, general muscular pain, recurrent abdominal discomfort, back pain, gastroesophageal reflux, recurrent headache, recurrent urinary problem, dizziness, breathlessness at rest) were assessed using structured questions in a blinded manner. Latent class analysis was applied to the data. Structural equation modeling was further performed in order to estimate the relative importance of genetic and environmental influences on class probability.
Latent class analysis resulted in a 5-class solution. Individuals in the first class did not show any health problems. Those assigned to the second, third, and fourth classes tended to have abnormal tiredness, gastrointestinal problems, and pain-related symptoms, respectively. Individuals in the fifth class had multiple symptoms to a greater extent than the other classes. All the five classes showed modest genetic influences (7 – 29% of the total variation) with gender differences except Class 3; however, the majority of influences on the class membership derived from unique environmental effects.
The findings suggested the necessity of re-defining the existing classification criteria for functional somatic syndromes in terms of single (uncomplicated) or multiple (complicated) syndromes. Environmental influences are important for the aetiology of functional somatic syndromes.
functional somatic syndromes; chronic fatigue syndrome; chronic widespread pain; irritable bowel syndrome; comorbidity; latent class analysis
Diet may be associated with risk of dementia and Alzheimer's disease (AD). We examined the association between fruit and vegetable consumption in midlife and risk for all types of dementia and AD.
Participants were 3,779 members of the Swedish Twin Registry who completed a diet questionnaire approximately 30 years prior to cognitive screening and full clinical evaluation for dementia as part of the HARMONY study. Among the participants, 355 twins were diagnosed with dementia. Among these, 81 twin pairs were discordant for dementia (50 discordant for AD). Data were analyzed with logistic regression for the entire sample using generalized estimating equations to adjust for relatedness of twins, and with conditional logistic regression for the co-twin control design.
In fully-adjusted models, a medium or great proportion of fruits and vegetables in the diet, compared to no or small, was associated with a decreased risk of dementia and AD. This effect was observed among women and those with angina. Similar, but non-significant, odds ratios were found in the co-twin control analyses.
Our findings suggest that higher fruit and vegetable consumption may reduce the risk of dementia, especially among women and those with angina pectoris in midlife.
dementia; Alzheimer's disease; diet; fruits and vegetables
We applied twin methodology to female and male twin pairs to further understand the nature of the relation between two behaviors associated with eating disorders—binge eating (BE) and night eating (NE) in an effort to determine the extent of overlap of genetic and environmental factors influencing liability to these behaviors. We calculated heritability estimates for males and females for each behavior and applied bivariate twin modeling to the female data to estimate the genetic and environmental correlation between these two traits. Data on BE and NE were derived from the Swedish Twin Study of Adults: Genes and Environment (STAGE) of the Swedish Twin Registry (STR; N = 11604). Prevalence estimates revealed sex differences with females more likely to endorse BE and males more likely to endorse NE. In males, we were only able to estimate univariate heritabilities due to small sample sizes: The heritability for BE was .74 [95% CI = (0.36, 0.93)] and for NE was .44 [95% CI = (0.24, 0.61)]. The best fitting bivariate model for females included additive genetic and unique environmental factors as well as the genetic correlation between BE and NE. Heritability estimates were 0.70 [95% CI = (0.26, 0.77)] for BE and 0.35 [95% CI = (0.17, 0.52)] for NE. The genetic correlation, 0.66 [95% CI = (0.48, 0.96)] suggests considerable overlap in the genetic factors influencing liability to BE and NE. In females, there is considerable overlap in the genetic factors that contribute to these traits, but the incomplete overlap allows for the influence of independent genetic and environmental factors as well. BE and NE in females are therefore best conceptualized as related but not identical traits.
The gene encoding the cholesteryl ester transfer protein (CETP) plays an integral role in lipid metabolism. We evaluated common genetic variation spanning CETP for association with cognitive decline as well as incident and prevalent dementia and Alzheimer disease risk. Data from four population-based twin studies and a case-control sample were included, encompassing an analysis sample of 1513 dementia cases and 2137 controls with available CETP genotypes and covariates. Memory and perceptual speed performance was assessed over 16 years in up to 1540 participants. Only sporadic associations were observed across 26 markers and were largely consistent with statistical noise. Polymorphism in CETP is unlikely to contribute to cognitive change or dementia risk.
Alzheimer disease; dementia; cognitive decline; CETP association; cholesteryl ester transfer protein