A burden of rare copy number variants in obsessive-compulsive disorder.

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, P = 1.77 × 10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P = 2.58 × 10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR = 1.19, P = 3.08 × 10-4), particularly deletions impacting loss-of-function intolerant genes (pLI >0.995, OR = 4.12, P = 2.54 × 10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60 × 10-3). In cases where sufficient clinical data were available (n = 1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P < 0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P = 0.02). The results demonstrate a contribution of rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.

ß2-Adrenoreceptor Agonists, Montelukast, and Parkinson Disease Risk.

OBJECTIVE: This study was undertaken to examine the association between montelukast use, ß2-adrenoreceptor (ß2AR) agonist use, and later Parkinson disease (PD). METHODS: We ascertained use of ß2AR agonists (430,885 individuals) and montelukast (23,315 individuals) from July 1, 2005 to June 30, 2007, and followed 5,186,886 PD-free individuals from July 1, 2007 to December 31, 2013 for incident PD diagnosis. We estimated hazard ratios and 95% confidence intervals using Cox regressions. RESULTS: We observed 16,383 PD cases during on average 6.1 years of follow-up. Overall, use of ß2AR agonists and montelukast were not related to PD incidence. A 38% lower PD incidence was noted among high-dose montelukast users when restricted to PD registered as the primary diagnosis. INTERPRETATION: Overall, our data do not support inverse associations between ß2AR agonists, montelukast, and PD. The prospect of lower PD incidence with high-dose montelukast exposure warrants further investigation, especially with adjustment for high-quality data on smoking. ANN NEUROL 2023;93:1023-1028.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Advanced biological ageing predicts future risk for neurological diagnoses and clinical examination findings.

Age is a dominant risk factor for some of the most common neurological diseases. Biological ageing encompasses interindividual variation in the rate of ageing and can be calculated from clinical biomarkers or DNA methylation data amongst other approaches. Here, we tested the hypothesis that a biological age greater than one's chronological age affects the risk of future neurological diagnosis and the development of abnormal signs on clinical examination. We analysed data from the Swedish Adoption/Twin Study of Aging (SATSA): a cohort with 3175 assessments of 802 individuals followed-up over several decades. Six measures of biological ageing were generated: two physiological ages (created from bedside clinical measurements and standard blood tests) and four blood methylation age measures. Their effects on future stroke, dementia or Parkinson's disease diagnosis, or development of abnormal clinical signs, were determined using survival analysis, with and without stratification by twin pairs. Older physiological ages were associated with ischaemic stroke risk; for example one standard deviation advancement in baseline PhenoAgePhys or KDMAgePhys residual increased future ischaemic stroke risk by 29.2% [hazard ratio (HR): 1.29, 95% confidence interval (CI) 1.06-1.58, P = 0.012] and 42.9% (HR 1.43, CI 1.18-1.73, P = 3.1 × 10-4), respectively. In contrast, older methylation ages were more predictive of future dementia risk, which was increased by 29.7% (HR 1.30, CI 1.07-1.57, P = 0.007) per standard deviation advancement in HorvathAgeMeth. Older physiological ages were also positively associated with future development of abnormal patellar or pupillary reflexes, and the loss of normal gait. Measures of biological ageing can predict clinically relevant pathology of the nervous system independent of chronological age. This may help to explain variability in disease risk between individuals of the same age and strengthens the case for trials of geroprotective interventions for people with neurological disorders.

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry.

AIMS: Cardiometabolic diseases (CMDs), including diabetes, heart disease, and stroke, are established risk factors for dementia, but their combined impact has been investigated only recently. This study aimed to examine the association between mid- and late-life cardiometabolic multimorbidity and dementia and explore the role of genetic background in this association. METHODS AND RESULTS: Within the Swedish Twin Registry, 17 913 dementia-free individuals aged ≥60 were followed for 18 years. CMDs [including age of onset in mid (60) or late (≥60) life] and dementia were ascertained from medical records. Cardiometabolic multimorbidity was defined as having ≥2 CMDs. Cox regression was used to estimate the CMD-dementia association in (i) a classical cohort study design and (ii) a co-twin study design involving 356 monozygotic and dizygotic pairs. By comparing the strength of the association in the two designs, the contribution of genetic background was estimated. At baseline, 3,312 (18.5%) participants had 1 CMD and 839 (4.7%) had ≥2 CMDs. Over the follow-up period, 3,020 participants developed dementia. In the classic cohort design, the hazard ratio (95% confidence interval) of dementia was 1.42 (1.27-1.58) for 1 CMD and 2.10 (1.73-2.57) for ≥2 CMDs. Dementia risk was stronger with mid-life as opposed to late-life CMDs. In the co-twin design, the CMD-dementia association was attenuated among monozygotic [0.99 (0.50-1.98)] but not dizygotic [1.55 (1.15-2.09)] twins, suggesting that the association was in part due to genetic factors common to both CMDs and dementia. CONCLUSION: Cardiometabolic multimorbidity, particularly in mid-life, is associated with an increased risk of dementia. Genetic background may underpin this association.

Dementia and mortality in older adults: A twin study.

INTRODUCTION: Dementia predicts increased mortality. We used case-control and co-twin control models to investigate genetic and shared environmental influences on this association. METHODS: Case-control design, including 987 twins with dementia and 2938 age- and sex-matched controls in the Swedish Twin Registry. Co-twin control design, including 90 monozygotic (MZ) and 288 dizygotic (DZ) twin pairs discordant for dementia. To test for genetic and environmental confounding, differences were examined in mortality risk between twins with dementia and their matched or co-twin controls. RESULTS: Twins with dementia showed greater mortality risk than age- and sex-matched controls (HR = 2.02 [1.86, 2.18]). Mortality risk is significantly elevated but attenuated substantially in discordant twin pairs, for example, comparing MZ twins with dementia to their co-twin controls (HR = 1.48 [1.08, 2.04]). DISCUSSION: Findings suggest that genetic factors partially confound the association between dementia and mortality and provide an alternative hypothesis to increased mortality due to dementia itself. Highlights We studied dementia and mortality in twin pairs discordant for dementia. People without dementia outlived people with dementia. Identical twins with dementia and their co-twin controls had similar survival time. Findings suggest genotype may explain the link between dementia and mortality.

Gastrointestinal biopsy of normal mucosa or nonspecific inflammation and risk of neurodegenerative disease: Nationwide matched cohort study.

BACKGROUND AND PURPOSE: Evidence has accumulated to support the early involvement of altered gastrointestinal (GI) function in neurodegenerative disease. However, risk of Alzheimer disease (AD) and Parkinson disease (PD) among individuals with a GI biopsy of normal mucosa or nonspecific inflammation is unknown. METHODS: This matched cohort study included all individuals in Sweden with a GI biopsy of normal mucosa (n = 480,346) or nonspecific inflammation (n = 655,937) during 1965-2016 (exposed group) as well as their individually matched population references and unexposed full siblings. A flexible parametric model and stratified Cox model were used to estimate hazard ratio (HR) and its 95% confidence interval (CI). RESULTS: Individuals with normal mucosa or nonspecific inflammation had a higher risk of AD and PD during the 20 years after biopsy. Compared with the population references, individuals with normal mucosa had an increased risk of AD (incidence rate [IR] difference = 13.53 per 100,000 person-years, HR [95% CI] = 1.15 [1.11-1.20]) and PD (IR difference = 6.72, HR [95% CI] = 1.16 [1.10-1.23]). Elevated risk was also observed for nonspecific inflammation regarding AD (IR difference = 13.28, HR [95% CI] = 1.11 [1.08-1.14]) and PD (IR difference = 6.83, HR [95% CI] = 1.10 [1.06-1.14]). Similar results were observed in subgroup and sensitivity analyses and when comparing with their unexposed siblings. CONCLUSIONS: Individuals with a GI biopsy of normal mucosa or nonspecific inflammation had an increased risk of AD and PD. This adds new evidence of the early involvement of GI dysfunction in neurodegenerative disease.

Remember This: Age Moderation of Genetic and Environmental Contributions to Verbal Episodic Memory from Midlife through Late Adulthood.

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall (N = 35,204 individuals; 21,792 twin pairs) and prose recall (N = 3,805 individuals; 2,028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning.

Comparison of two different frailty scales in the longitudinal Swedish Adoption/Twin Study of Aging (SATSA).

AIMS: Although up to 25% of older adults are frail, assessing frailty can be difficult, especially in registry data. This study evaluated the utility of a code-based frailty score in registry data by comparing it to a gold-standard frailty score to understand how frailty can be quantified in population data and perhaps better addressed in healthcare. METHODS: We compared the Hospital Frailty Risk Score (HFRS), a frailty measure based on 109 ICD codes, to a modified version of the Frailty Index (FI) Frailty Index (FI), a self-report frailty measure, and their associations with all-cause mortality both cross-sectionally and longitudinally (follow-up = 36 years) in a Swedish cohort study (n = 1368). RESULTS: The FI and HFRS were weakly correlated (rho = 0.11, p < 0.001). Twenty-two percent (n = 297) of participants were considered frail based on published cut-offs of either measure. Only 3% (n = 35) of participants were classified as frail by both measures; 4% (n = 60) of participants were considered frail by only the HFRS; and 15% (n = 202) of participants were considered frail based only on the FI. Frailty as measured by the HFRS showed greater variance and no clear increase or decrease with age, while frailty as measured by the FI increased steadily with age. In adjusted Cox proportional hazard models, baseline HFRS frailty (HR = 1.17, 95% CI 0.92, 1.49) was not statistically significantly associated with mortality, while FI frailty was (HR = 2.89, 95% CI 1.61, 2.23). These associations were modified by age and sex. CONCLUSIONS: The HFRS may not capture the full spectrum of frailty among community-dwelling individuals, particularly at younger ages, in Swedish registry data.

Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy.

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

Adiposity and the risk of dementia: mediating effects from inflammation and lipid levels.

While midlife adiposity is a risk factor for dementia, adiposity in late-life appears to be associated with lower risk. What drives the associations is poorly understood, especially the inverse association in late-life. Using results from genome-wide association studies, we identified inflammation and lipid metabolism as biological pathways involved in both adiposity and dementia. To test if these factors mediate the effect of midlife and/or late-life adiposity on dementia, we then used cohort data from the Swedish Twin Registry, with measures of adiposity and potential mediators taken in midlife (age 40-64, n = 5999) or late-life (age 65-90, n = 7257). Associations between body-mass index (BMI), waist-hip ratio (WHR), C-reactive protein (CRP), lipid levels, and dementia were tested in survival and mediation analyses. Age was used as the underlying time scale, and sex and education included as covariates in all models. Fasting status was included as a covariate in models of lipids. One standard deviation (SD) higher WHR in midlife was associated with 25% (95% CI 2-52%) higher dementia risk, with slight attenuation when adjusting for BMI. No evidence of mediation through CRP or lipid levels was present. After age 65, one SD higher BMI, but not WHR, was associated with 8% (95% CI 1-14%) lower dementia risk. The association was partly mediated by higher CRP, and suppressed when high-density lipoprotein levels were low. In conclusion, the negative effects of midlife adiposity on dementia risk were driven directly by factors associated with body fat distribution, with no evidence of mediation through inflammation or lipid levels. There was an inverse association between late-life adiposity and dementia risk, especially where the body's inflammatory response and lipid homeostasis is intact.

Predictors of resilience in older adults with lower limb osteoarthritis and persistent severe pain.

BACKGROUND: Resilience refers to the process in which people function well despite adversity. Persistent severe pain may be considered an adversity in people with lower limb osteoarthritis (LLOA). The objectives of this study are: (1) to identify what proportion of older adults with LLOA and persistent severe pain show good functioning; and (2) to explore predictors of resilience. METHODS: Data from the European Project on OSteoArthritis (EPOSA) were used involving standardized data from six European population-based cohort studies. LLOA is defined as clinical knee and/or hip osteoarthritis. Persistent severe pain is defined as the highest tertile of the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index both at baseline and follow-up. Resilience is defined as good physical, mental or social functioning at follow-up despite having LLOA with persistent severe pain. RESULTS: In total, 95 (14.9%) out of 638 individuals with LLOA had persistent severe pain. Among these, 10 (11.0%), 54 (57.4%) and 49 (53.8%) had good physical, mental and social functioning, respectively. Only 4 individuals (4.5%) were resilient in all three domains of functioning. Younger age, male sex, higher education, higher mastery, smoking and alcohol use, higher physical activity levels, absence of chronic diseases, and more contacts with friends predicted resilience in one or more domains of functioning. CONCLUSIONS: Few people with LLOA and persistent severe pain showed good physical functioning and about half showed good mental or social functioning. Predictors of resilience differed between domains, and might provide new insights for treatment.

Attention-deficit/hyperactivity disorder and Alzheimer's disease and any dementia: A multi-generation cohort study in Sweden.

INTRODUCTION: We examined the extent to which attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder, is linked with Alzheimer's disease (AD) and any dementia, neurodegenerative diseases, across generations. METHODS: A nationwide cohort born between 1980 and 2001 (index persons) were linked to their biological relatives (parents, grandparents, uncles/aunts) using Swedish national registers. We used Cox models to examine the cross-generation associations. RESULTS: Among relatives of 2,132,929 index persons, 3042 parents, 171,732 grandparents, and 1369 uncles/aunts had a diagnosis of AD. Parents of individuals with ADHD had an increased risk of AD (hazard ratio 1.55, 95% confidence interval 1.26-1.89). The associations attenuated but remained elevated in grandparents and uncles/aunts. The association for early-onset AD was stronger than late-onset AD. Similar results were observed for any dementia. DISCUSSION: ADHD is associated with AD and any dementia across generations. The associations attenuated with decreasing genetic relatedness, suggesting shared familial risk between ADHD and AD.

A healthy lifestyle mitigates the risk of heart disease related to type 2 diabetes: a prospective nested case-control study in a nationwide Swedish twin cohort.

AIMS/HYPOTHESIS: We aimed to examine the association between type 2 diabetes and major subtypes of heart disease, to assess the role of genetic and early-life familial environmental factors in this association and to explore whether and to what extent a healthy lifestyle mitigates the risk of heart disease related to type 2 diabetes. METHODS: In this prospective nested case-control study based on the Swedish Twin Registry, 41,463 twin individuals who were aged ≥40 and heart disease-free were followed up for 16 years (from 1998 to 2014) to detect incident heart disease. Type 2 diabetes was ascertained from self-report, the National Patient Registry and glucose-lowering medication use. Heart disease diagnosis (including coronary heart disease, cardiac arrhythmias and heart failure) and onset age were identified from the National Patient Registry. Healthy lifestyle-related factors consisted of being a non-smoker, no/mild alcohol consumption, regular physical activity and being non-overweight. Participants were divided into three groups according to the number of lifestyle-related factors: (1) unfavourable (participants who had no or only one healthy lifestyle factor); (2) intermediate (any two or three); and (3) favourable (four). Generalised estimating equation models for unmatched case-control design and conditional logistic regression for co-twin control design were used in data analyses. RESULTS: Of all participants, 2304 (5.5%) had type 2 diabetes at baseline. During the observation period, 9262 (22.3%) had any incident heart disease. In unmatched case-control analyses and co-twin control analyses, the multi-adjusted OR and 95% CI of heart disease related to type 2 diabetes was 4.36 (3.95, 4.81) and 4.89 (3.88, 6.16), respectively. The difference in ORs from unmatched case-control analyses vs co-twin control analyses was statistically significant (OR 1.57; 95% CI 1.42, 1.73; p < 0.001). In stratified analyses by type 2 diabetes, compared with an unfavourable lifestyle, an intermediate lifestyle or a favourable lifestyle was associated with a significant 32% (OR 0.68; 95% CI 0.49, 0.93) or 56% (OR 0.44; 95% CI 0.30, 0.63) decrease in heart disease risk among patients with type 2 diabetes, respectively. There were significant additive and multiplicative interactions between lifestyle and type 2 diabetes on heart disease. CONCLUSIONS/INTERPRETATION: Type 2 diabetes is associated with more than fourfold increased risk of heart disease. The association still remains statistically significant, even after fully controlling for genetic and early-life familial environmental factors. However, greater adherence to a healthy lifestyle may significantly mitigate the risk of heart disease related to type 2 diabetes. Graphical abstract.

Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness.

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

Frailty and the risk of dementia: is the association explained by shared environmental and genetic factors?

BACKGROUND: Frailty has been identified as a risk factor for cognitive impairment and dementia. However, it is not known whether familial factors, such as genetics and shared environmental factors, underlie this association. We analyzed the association between frailty and the risk of dementia in a large twin cohort and examined the role of familial factors in the association. METHODS: The Rockwood frailty index (FI) based on 44 health deficits was used to assess frailty. The population-level association between FI and the risk of all-cause dementia was analyzed in 41,550 participants of the Screening Across the Lifespan Twin (SALT) study (full sample, aged 41-97 years at baseline), using Cox and competing risk models. A subsample of 10,487 SALT participants aged 65 and older who received a cognitive assessment (cognitive sample) was used in a sensitivity analysis to assess the effect of baseline cognitive level on the FI-dementia association. To analyze the influence of familial effects on the FI-dementia association, a within-pair analysis was performed. The within-pair model was also used to assess whether the risk conferred by frailty varies by age at FI assessment. RESULTS: A total of 3183 individuals were diagnosed with dementia during the 19-year follow-up. A 10% increase in FI was associated with an increased risk of dementia (hazard ratio [HR] 1.17 (95% confidence interval [CI] 1.07, 1.18)) in the full sample adjusted for age, sex, education, and tobacco use. A significant association was likewise found in the cognitive sample, with an HR of 1.13 (95% CI 1.09, 1.20), adjusted for age, sex, and cognitive level at baseline. The associations were not attenuated when adjusted for APOE ɛ4 carrier status or considering the competing risk of death. After adjusting for familial effects, we found no evidence for statistically significant attenuation of the effect. The risk conferred by higher FI on dementia was constant after age 50 until very old age. CONCLUSIONS: A higher level of frailty predicts the risk of dementia and the association appears independent of familial factors. Targeting frailty might thus contribute to preventing or delaying dementia.

Mediterranean Dietary Pattern at Middle Age and Risk of Parkinson's Disease: A Swedish Cohort Study.

BACKGROUND: The Mediterranean diet has been proposed to protect against neurodegeneration. OBJECTIVES: The aim of this study was to assess the association of adherence to Mediterranean dietary pattern (MDP) at middle age with risk for Parkinson's disease (PD) later in life. METHOD: In a population-based cohort of >47,000 Swedish women, information on diet was collected through a food frequency questionnaire during 1991-1992, from which adherence to MDP was calculated. We also collected detailed information on potential confounders. Clinical diagnosis of PD was ascertained from the Swedish National Patient Register through 2012. RESULTS: We observed an inverse association between adherence to MDP and PD, multivariable hazard ratio of 0.54 (95% confidence interval: 0.30-0.98), comparing high with low adherence. The association was noted primarily from age 65 years onward. One unit increase in the adherence score was associated with a 29% lower risk for PD at age ≥ 65 years (95% confidence interval: 0.57-0.89). CONCLUSION: Higher adherence to a Mediterranean diet at middle age was associated with lower risk for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association Between Microscopic Colitis and Parkinson's Disease in a Swedish Population.

BACKGROUND: Gastrointestinal inflammation has been linked with Parkinson's disease (PD). Microscopic colitis (MC) is an intestinal inflammatory disease with unknown relationship with PD. OBJECTIVE: This study aimed to examine the association of MC with PD risk. METHODS: In this nationwide matched cohort study in Sweden, PD incidence was compared between 12,609 patients with histologically confirmed MC and a matched population cohort of 58,879 MC-free individuals and a sibling cohort comprising all unaffected siblings of the MC patients (NMC /NSibling  = 6281/12,351). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS: During a mean follow-up of ~7 years, we identified 449 incident PD diagnoses among the MC patients and the population cohort. Overall, MC was associated with an adjusted HR of 1.76 for PD, but the association attenuated substantially during follow-up. In the time-varying effects model, PD hazard was 3.45-fold (95% CI: 2.42, 4.93) higher during the first 2 years after biopsy and 1.80-fold (95% CI: 1.23, 2.64) higher during the following 3 years among MC versus MC-free individuals but was not different beyond 5 years after biopsy (HR: 1.03; 95% CI: 0.68, 1.54). This temporal pattern of MC-PD associations persisted when comparing MC patients to their siblings. In a post hoc case-control analysis, we also detected a strong association between MC and preexisting PD (odds ratio: 3.46; 95% CI: 2.91, 4.12). CONCLUSIONS: Our findings suggest that MC may not be a risk factor for PD; instead, it may co-occur with PD as a comorbidity or develop after a diagnosis of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (ß = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (ß = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.

Frailty trajectories in three longitudinal studies of aging: Is the level or the rate of change more predictive of mortality?

BACKGROUND: frailty shows an upward trajectory with age, and higher levels increase the risk of mortality. However, it is less known whether the shape of frailty trajectories differs by age at death or whether the rate of change in frailty is associated with mortality. OBJECTIVES: to assess population frailty trajectories by age at death and to analyse whether the current level of the frailty index (FI) i.e. the most recent measurement or the person-specific rate of change is more predictive of mortality. METHODS: 3,689 individuals from three population-based cohorts with up to 15 repeated measurements of the Rockwood frailty index were analysed. The FI trajectories were assessed by stratifying the sample into four age-at-death groups: <70, 70-80, 80-90 and >90 years. Generalised survival models were used in the survival analysis. RESULTS: the FI trajectories by age at death showed that those who died at <70 years had a steadily increasing trajectory throughout the 40 years before death, whereas those who died at the oldest ages only accrued deficits from age ~75 onwards. Higher level of FI was independently associated with increased risk of mortality (hazard ratio 1.68, 95% confidence interval 1.47-1.91), whereas the rate of change was no longer significant after accounting for the current FI level. The effect of the FI level did not weaken with time elapsed since the last measurement. CONCLUSIONS: Frailty trajectories differ as a function of age-at-death category. The current level of FI is a stronger marker for risk stratification than the rate of change.