Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight.

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.

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.

Sensitivity to Noise Following a Mild Traumatic Brain Injury: A Longitudinal Study.

OBJECTIVE: To describe changes in the prevalence and clinical correlates of noise sensitivity (NS) in mild traumatic brain injury (mTBI) across a 12-month period and to determine whether NS at an early stage of recovery has predictive value for later postconcussive symptoms. SETTING: A mixed urban and rural region of New Zealand. PARTICIPANTS: Data for 341 adults (201 males, 140 females; age range from 16 to 91 years) were extracted from a 1-year TBI incidence, and outcomes study was conducted in New Zealand. DESIGN: Secondary analysis of data from a community-based, longitudinal population study of an mTBI incidence cohort collected within 1 week of injury (baseline) and at 1, 6, and 12 months postinjury. MAIN MEASURES: Measures at baseline (within 2 weeks of the injury) and 1, 6, and 12 months included the Rivermead Post-concussion Symptoms Questionnaire and its NS item, the Hospital Depression and Anxiety Scale, and the computerized CNS-Vital Signs neurocognitive test. RESULTS: NS progressively declined postinjury, from 45% at baseline to 28% at 12 months. In turn, NS showed itself as a significant predictor of future postconcussive symptoms. CONCLUSION: Taken together with previous research, the findings of the current study indicate that NS may have clinical utility in flagging vulnerability to persistent postconcussive symptoms.

Triplets, birthweight, and handedness.

The mechanisms behind handedness formation in humans are still poorly understood. Very low birthweight is associated with higher odds of left-handedness, but whether this is due to low birthweight itself or premature birth is unknown. Handedness has also been linked to development, but the role of birthweight behind this association is unclear. Knowing that birthweight is lower in multiple births, triplets being about 1.5 kg lighter in comparison with singletons, and that multiples have a higher prevalence of left-handedness than singletons, we studied the association between birthweight and handedness in two large samples consisting exclusively of triplets from Japan (n = 1,305) and the Netherlands (n = 947). In both samples, left-handers had significantly lower birthweight (Japanese mean = 1,599 g [95% confidence interval (CI): 1,526-1,672 g]; Dutch mean = 1,794 g [95% CI: 1,709-1,879 g]) compared with right-handers (Japanese mean = 1,727 g [95% CI: 1,699-1,755 g]; Dutch mean = 1,903 g [95% CI: 1,867-1,938 g]). Within-family and between-family analyses both suggested that left-handedness is associated with lower birthweight, also when fully controlling for gestational age. Left-handers also had significantly delayed motor development and smaller infant head circumference compared with right-handers, but these associations diluted and became nonsignificant when controlling for birthweight. Our study in triplets provides evidence for the link between low birthweight and left-handedness. Our results also suggest that developmental differences between left- and right-handers are due to a shared etiology associated with low birthweight.

The Epidemiology of Noise Sensitivity in New Zealand.

BACKGROUND: Sensitivity to noise, or nuisance sounds that interrupt relaxation and task-related activities, has been shown to vary significantly across individuals. The current study sought to uncover predictors of noise sensitivity, focussing on possible social and cultural determinants, including social position, education, ethnicity, gender, and the presence of an illness. METHOD: Data were collected from 746 New Zealand adults residing in 6 areas differentiated by social position. Participants responded to questions probing personal characteristics, noise sensitivity, illness, neighbourhood problems, and noise annoyance. It was hypothesized that those in high-deprivation areas and/or experiencing illness report higher levels of noise sensitivity. RESULTS: Approximately 50 and 10% of the participants reported being moderately or very noise sensitive, respectively. Significant predictors of noise sensitivity included age, length of residence, level of social deprivation, and self-reported illness. CONCLUSION: There is evidence of social determinants of noise sensitivity, including social position and residential factors.

FinnTwin16: A Longitudinal Study from Age 16 of a Population-Based Finnish Twin Cohort.

The purpose of this review is to provide a detailed and updated description of the FinnTwin16 (FT16) study and its future directions. The Finnish Twin Cohort comprises three different cohorts: the Older Twin Cohort established in the 1970s and the FinnTwin12 and FT16 initiated in the 1990s. FT16 was initiated in 1991 to identify the genetic and environmental precursors of alcoholism, but later the scope of the project expanded to studying the determinants of various health-related behaviors and diseases in different stages of life. The main areas addressed are alcohol use and its consequences, smoking, physical activity, overall physical health, eating behaviors and eating disorders, weight development, obesity, life satisfaction and personality. To date, five waves of data collection have been completed and the sixth is now planned. Data from the FT16 cohort have contributed to several hundred studies and many substudies, with more detailed phenotyping and collection of omics data completed or underway. FT16 has also contributed to many national and international collaborations.

FinnTwin12 Cohort: An Updated Review.

This review offers an update on research conducted with FinnTwin12 (FT12), the youngest of the three Finnish Twin Cohorts. FT12 was designed as a two-stage study. In the first stage, we conducted multiwave questionnaire research enrolling all eligible twins born in Finland during 1983-1987 along with their biological parents. In stage 2, we intensively studied a subset of these twins with in-school assessments at age 12 and semistructured poly-diagnostic interviews at age 14. At baseline, parents of intensively studied twins were administered the adult version of the interview. Laboratory studies with repeat interviews, neuropsychological tests, and collection of DNA were made of intensively studied twins during follow-up in early adulthood. The basic aim of the FT12 study design was to obtain information on individual, familial and school/neighborhood risks for substance use/abuse prior to the onset of regular tobacco and alcohol use and then track trajectories of use and abuse and their consequences into adulthood. But the longitudinal assessments were not narrowly limited to this basic aim, and with multiwave, multirater assessments from ages 11 to 12, the study has created a richly informative data set for analyses of gene-environment interactions of both candidate genes and genomewide measures with measured risk-relevant environments. Because 25 years have elapsed since the start of the study, we are planning a fifth-wave follow-up assessment.

Early adolescent aggression predicts antisocial personality disorder in young adults: a population-based study.

Modestly prevalent in the general population (~ 4%), but highly prevalent in prison populations (> 40%), the diagnosis of antisocial personality disorder (ASPD) involves aggression as one of several possible criteria. Using multiple informants, we aimed to determine if general aggression, as well as direct and indirect subtypes, assessed in early adolescence (ages 12, 14) predict young adulthood ASPD in a population-based sample. Using data from a Finnish population-based longitudinal twin cohort study with psychiatric interviews available at age 22 (N = 1347), we obtained DSM-IV-based ASPD diagnoses. Aggression measures from ages 12 (parental and teacher ratings) and 14 (teacher, self, and co-twin ratings) were used to calculate odds ratios (OR) of ASPD from logistic regression models and the area under the curve (AUC) from receiver operating characteristic curve analysis. Analyses were adjusted for sex, age, and family structure. All informants' aggression ratings were significant (p < 0.05) predictors of ASPD (OR range 1.3-1.8; AUC range 0.65-0.72). Correlations between informants ranged from 0.13 to 0.33. Models including two or more aggression ratings, particularly age 14 teacher and self ratings, more accurately predicted ASPD (AUC: 0.80; 95% confidence interval 0.73-0.87). Direct aggression rated by all informants significantly predicted ASPD (OR range 1.4-1.9), whereas only self-rated indirect aggression was significantly associated with ASPD (OR = 1.4). Across different informants, general and direct aggression at ages 12 and 14 predicted ASPD in a population-based sample. Psychiatric, social, and parenting interventions for ASPD prevention should focus on children and adolescents with high aggression levels, with an aim to gather information from multiple informants.

Predictive Association of Smoking with Depressive Symptoms: a Longitudinal Study of Adolescent Twins.

Longitudinal, genetically informative studies of the association between cigarette smoking and depressive symptoms among adolescents are limited. We examined the longitudinal association of cigarette smoking with subsequent depressive symptoms during adolescence in a Finnish twin cohort. We used prospective data from the population-based FinnTwin12 study (maximum N = 4152 individuals, 1910 twin pairs). Current smoking status and a number of lifetime cigarettes smoked were assessed at the age of 14 and depressive symptoms at the age of 17. Negative binomial regression was conducted to model the association between smoking behavior and subsequent depressive symptoms among individuals, and within-pair analyses were conducted to control for unmeasured familial confounding. Analyses were adjusted for age, sex, school grades, drinking alcohol to intoxication, health status, family structure, parental education, and smoking, as well as for pre-existing depressiveness. The results of the individual-level analyses showed that cigarette smoking at the age of 14 predicted depressive symptoms at the age of 17. Compared to never smokers, those who had smoked over 50 cigarettes (incidence rate ratio, IRR = 1.43, 95% CI 1.28-1.60) and regular smokers (IRR = 1.46, 95% CI 1.32-1.62) had higher depression scores. The associations were attenuated when adjusted for measured covariates and further reduced in within-pair analyses. In the within-pair results, the estimates were lower within monozygotic (MZ) pairs compared to dizygotic (DZ) pairs, suggesting that shared genetic factors contribute to the associations observed in individual-based analyses. Thus, we conclude that cigarette smoking is associated with subsequent depressive symptoms during adolescence, but the association is not independent of measured confounding factors and shared genetic influences.

Education in Twins and Their Parents Across Birth Cohorts Over 100 years: An Individual-Level Pooled Analysis of 42-Twin Cohorts.

Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990-1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.

Twin's Birth-Order Differences in Height and Body Mass Index From Birth to Old Age: A Pooled Study of 26 Twin Cohorts Participating in the CODATwins Project.

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

Association between education and future leisure-time physical inactivity: a study of Finnish twins over a 35-year follow-up.

BACKGROUND: Education is associated with health related lifestyle choices including leisure-time physical inactivity. However, the longitudinal associations between education and inactivity merit further studies. We investigated the association between education and leisure-time physical inactivity over a 35-year follow-up with four time points controlling for multiple covariates including familial confounding. METHODS: This study of the population-based Finnish Twin Cohort consisted of 5254 twin individuals born in 1945-1957 (59 % women), of which 1604 were complete same-sexed twin pairs. Data on leisure-time physical activity and multiple covariates was available from four surveys conducted in 1975, 1981, 1990 and 2011 (response rates 72 to 89 %). The association between years of education and leisure-time physical inactivity (<1.5 metabolic equivalent hours/day) was first analysed for each survey. Then, the role of education was investigated for 15-year and 35-year inactivity periods in the longitudinal analyses. The co-twin control design was used to analyse the potential familial confounding of the effects. All analyses were conducted with and without multiple covariates. Odds Ratios (OR) with 95 % Confidence Intervals (CI) were calculated using logistic and conditional (fixed-effects) regression models. RESULTS: Each additional year of education was associated with less inactivity (OR 0.94 to 0.95, 95 % CI 0.92, 0.99) in the cross-sectional age- and sex-adjusted analyses. The associations of education with inactivity in the 15- and 35-year follow-ups showed a similar trend: OR 0.97 (95 % CI 0.93, 1.00) and OR 0.94 (95 % CI 0.91, 0.98), respectively. In all co-twin control analyses, each year of higher education was associated with a reduced likelihood of inactivity suggesting direct effect (i.e. independent from familial confounding) of education on inactivity. However, the point estimates were lower than in the individual-level analyses. Adjustment for multiple covariates did not change these associations. CONCLUSIONS: Higher education is associated with lower odds of leisure-time physical inactivity during the three-decade follow-up. The association was found after adjusting for several confounders, including familial factors. Hence, the results point to the conclusion that education has an independent role in the development of long-term physical inactivity and tailored efforts to promote physical activity among lower educated people would be needed throughout adulthood.

Familial Risk and Heritability of Cancer Among Twins in Nordic Countries.

IMPORTANCE: Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE: To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N = 203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES: Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES: The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin's development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS: A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE: In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

Higher Prevalence of Left-Handedness in Twins? Not After Controlling Birth Time Confounders.

Pregnancy- and birth-related factors may have an effect on handedness. Compared with singletons, twins have a lower birth weight, shorter gestational age, and are at higher risk for birth complications. We tested whether the prevalence of left-handedness is higher among twins than singletons, and if so, whether that difference is fully explained by pregnancy and birth-related differences between twins and singletons. We analyzed Finnish population-based datasets; included were 8,786 twins and 5,892 singletons with information on birth weight (n = 12,381), Apgar scores (n = 11,129), and gestational age (n = 11,811). Two twin cohorts were involved: FinnTwin12 included twins born during 1983-1987, and FinnTwin16 included twins born during 1974-1979. We had two comparison groups of singletons: 4,101 individuals born during 1986-1988 and enrolled in the Helsinki Ultrasound Trial, and 1,791 individuals who were partners of FinnTwin16 twins. We used logistic regression models with writing hand as the outcome for comparison and evaluating effects of covariates. Left-handedness was more common in twins (9.67%) than in singletons (8.27%; p = .004). However, Apgar scores were associated with handedness, and after controlling for covariates, we found no difference in the prevalence of left-handedness between twins and singletons. Increased left-handedness among twins, often reported by others, was evident in our data, but only among our older twin cohorts, and that association disappeared after removing effects of perinatal covariates.

Elucidating the relationship between noise sensitivity and personality.

Sensitivity to unwanted sounds is common in general and clinical populations. Noise sensitivity refers to physiological and psychological internal states of an individual that increase the degree of reactivity to noise in general. The current study investigated the relationship between the Big Five personality dimensions and noise sensitivity using the 240-item NEO Personality Inventory (NEO-PI) and 35-item The Noise-Sensitivity-Questionnaire (NoiSeQ) scales, respectively. Overall, the Big Five accounted for 33% of the variance in noise sensitivity, with the Introversion-Extroversion dimension explaining the most variability. Furthermore, the Big Five personality dimensions (neuroticism, extroversion, openness, agreeableness, and conscientiousness) had an independent effect on noise sensitivity, which were linear. However, additional analyses indicated that the influence of gender and age must be considered when examining the relationship between personality and noise sensitivity. The findings caution against pooling data across genders, not controlling for age, and using personality dimensions in isolation.

The association of noise sensitivity with music listening, training, and aptitude.

After intensive, long-term musical training, the auditory system of a musician is specifically tuned to perceive musical sounds. We wished to find out whether a musician's auditory system also develops increased sensitivity to any sound of everyday life, experiencing them as noise. For this purpose, an online survey, including questionnaires on noise sensitivity, musical background, and listening tests for assessing musical aptitude, was administered to 197 participants in Finland and Italy. Subjective noise sensitivity (assessed with the Weinstein's Noise Sensitivity Scale) was analyzed for associations with musicianship, musical aptitude, weekly time spent listening to music, and the importance of music in each person's life (or music importance). Subjects were divided into three groups according to their musical expertise: Nonmusicians (N = 103), amateur musicians (N = 44), and professional musicians (N = 50). The results showed that noise sensitivity did not depend on musical expertise or performance on musicality tests or the amount of active (attentive) listening to music. In contrast, it was associated with daily passive listening to music, so that individuals with higher noise sensitivity spent less time in passive (background) listening to music than those with lower sensitivity to noise. Furthermore, noise-sensitive respondents rated music as less important in their life than did individuals with lower sensitivity to noise. The results demonstrate that the special sensitivity of the auditory system derived from musical training does not lead to increased irritability from unwanted sounds. However, the disposition to tolerate contingent musical backgrounds in everyday life depends on the individual's noise sensitivity.

Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory.

Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.

The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.

BACKGROUND: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. METHODS AND FINDINGS: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n  =  198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p  =  0.001). CONCLUSIONS: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

Midlife cardiovascular risk factors and late cognitive impairment.

Cardiovascular risk factors increase the risk of dementia in later life. The aims of the current study were to assess the effect of multiple midlife cardiovascular risk factors on the risk of cognitive impairment in later life, and to assess the validity of the previously suggested CAIDE Study risk score predicting dementia risk 20 years later. A total of 2,165 Finnish twins were followed and at the end of the follow-up their cognitive status was assessed with a validated telephone interview. The assessment of the risk factors at baseline was based on a self-report questionnaire. Relative risk ratios (RR) were calculated and receiver operating characteristic analyses performed. Midlife obesity (RR 2.42, 95 % CI 1.47-3.98), hypertension (RR 1.38, 95 % CI 1.01-1.88) and low leisure time physical activity (RR 2.52, 95 % CI 1.10-5.76) increased the risk of cognitive impairment after a mean follow-up of 22.6 ± 2.3 years. Hypercholesterolemia did not significantly increase the risk (RR 1.52, 95 % CI 0.92-2.51). Overweight individuals who gained more than 10 % weight between 1981 and 1990 had an increased risk of cognitive impairment (RR 4.27, 95 % CI 1.62-11.2). The CAIDE Study risk score combining various individual risk factors had an area-under-curve of 0.74 (95 % CI 0.69-0.79, n = 591), and there was a strong association between an increasing risk score and the risk of cognitive impairment. The results indicate that multiple midlife cardiovascular risk factors increase the risk of cognitive impairment in later life. Also, a risk score including easily measurable midlife factors predicts an individual's cognitive impairment risk well.

Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits.

INTRODUCTION: The role of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25 in the etiology of nicotine dependence (ND) is still being defined. In this study, we included all 15 tagging single nucleotide polymorphisms (SNPs) within the CHRNA5-CHRNA3-CHRNB4 cluster and tested associations with 30 smoking-related phenotypes. METHODS: The study sample was ascertained from the Finnish Twin Cohort study. Twin pairs born 1938-1957 and concordant for a history of cigarette smoking were recruited along with their family members (mainly siblings), as part of the Nicotine Addiction Genetics consortium. The study sample consisted of 1,428 individuals (59% males) from 735 families, with mean age 55.6 years. RESULTS: We detected multiple novel associations for ND. DSM-IV ND symptoms associated significantly with the proxy SNP Locus 1 (rs2036527, p = .000009) and Locus 2 (rs578776, p = .0001) and tolerance factor of the Nicotine Dependence Syndrome Scale (NDSS) showed suggestive association to rs11636753 (p = .0059), rs11634351 (p = .0069), and rs1948 (p = .0071) in CHRNB4. Furthermore, we report significant association with DSM-IV ND diagnosis (rs2036527, p = .0003) for the first time in a Caucasian population. Several SNPs indicated suggestive association for traits related to ages at smoking initiation. Also, rs11636753 in CHRNB4 showed suggestive association with regular drinking (p = .0029) and the comorbidity of depression and ND (p = .0034). CONCLUSIONS: We demonstrate novel associations of DSM-IV ND symptoms and the NDSS tolerance subscale. Our results confirm and extend association findings for other ND measures. We show pleiotropic effects of this gene cluster on multiple measures of ND and also regular drinking and the comorbidity of ND and depression.