Genetic Dissection of the Pathophysiology of Cardiovascular Risk Factors

Background: Genome-wide association studies (GWAS) have uncovered a pleth- ora of biological information behind complex diseases. Findings from the GWAS and subsequent functional studies can facilitate drug development by identifying novel drug targets and predicting side-effects. Aims: This thesis investigates the ability of genome-wide data to reveal potential mechanisms and treatments for cardiovascular diseases using a gene-environment interaction study, combined use of mice and human data, and detailed molecular methods involving intermediate phenotype data. Participants and methods: This thesis is based on data from The Cardiovascular Risk Factors in Young Finns Study, the Special Turku Coronary Risk Factor In- tervention Project, and national FINRISK surveys. Results: The gene-environment design was able to identify one potential drug tar- get for lowering LDL-cholesterol levels. The effect of dietary fat on serum LDL- cholesterol was more pronounced in subjects with rs9364628-TT. Combined anal- yses of mice and human data were able to identify the melanocortin 1 receptor as a potential drug target for improving cardiovascular health. By using cytokines as detailed molecular intermediate phenotypes, we were able to identify 27 loci (17 novel) associated with concentrations of circulating cytokines. Conclusions: Combined used of animal and human data and use of detailed mo- lecular intermediate phenotypes can be efficiently used to identify drug targets. More research is needed to elucidate whether gene-environment studies can be utilized in drug discovery.Tausta: Viimeaikaiset edistysaskeleet genetiikassa ja tietokonealalla ovat mahdol- listaneet genominlaajuisten assosiaatiotutkimusten toteuttamisen. Tutkimustulos- ten odotetaan auttavan lääkekehitystä. Tavoite: Väitöskirjatyön tavoitteena on arvioida, kuinka ihmisiin keskittyvä ge- neettinen tutkimus voisi auttaa osoittamaan uusia lääkevaikutuskohteita sydän- ja verisuonitautien ja niiden riskitekijöiden hoitamiseksi. Menetelmät: Aineistona käytetään Lasten Sepelvaltimotaudin Riskitekijät (LA- SERI) –tutkimusta, Sepelvaltimotaudin Riskitekijöiden Interventio Projekti -tutkimusta (STRIP) ja FINRISK-tutkimuksia. Tulokset: Geeni-ympäristö – interaktiotutkimuksessa havaittiin yksi lokus (PARK2), jossa sijaitseva variantti sääteli ravinnon rasvahappokoostumuksen vai- kutusta verenkierrossa vallitsevaan LDL-kolesterolikonsentraatioon. Ravinnon rasvan laadun vaikutus oli korostunut henkilöillä, joilla oli rs9364628-TT alleeli. Toisessa osatyössä hyödynnettiin kliinistä ja eläintutkimusta. Työssä voitiin osoit- taa, että MC1R-reseptorin toiminta vaikuttaa verisuoniterveyteen hiirillä ja ihmi- sillä. Kolmannessa osatyössä tunnistettiin 27 lokusta (17 uutta), jotka olivat yhtey- dessä vähintään yhteen tutkituista 41 sytokiinista tai kasvutekijästä. Tuloksia voi- daan hyödyntää kehitettäessä hoitomuotoja Crohnin tautiin, MS-tautiin, Behcetin tautiin´ja keliakiaan. Johtopäätökset: Yhdistämällä dataa kliinisistä tutkimuksista ja eläintutkimuk- sista sekä tutkimalla yksityiskohtaisia molekyylitason fenotyyppejä voidaan löytää potentiaalisia lääkevaikutuskohteita. Lisätutkimuksia tarvitaan geeni-ympäristö – interaktiotutkimusten merkityksen arvioimiseksi lääkekehityksessä

Does social intolerance vary according to cognitive styles, genetic cognitive capacity, or education?

BACKGROUND: Low education, low cognitive abilities, and certain cognitive styles are suggested to predispose to social intolerance and prejudices. Evidence is, however, restricted by comparatively small samples, neglect of confounding variables and genetic factors, and a narrow focus on a single sort of prejudice. We investigated the relationships of education, polygenic cognitive potential, cognitive performance, and cognitive styles with social intolerance in adulthood over a 15-year follow-up. METHODS: We used data from the prospective population-based Young Finns Study (n = 960-1679). Social intolerance was evaluated with the Social Intolerance Scale in 1997, 2001, and 2011; cognitive performance with the Cambridge Neuropsychological Test Automated Battery in 2011; cognitive styles in 1997; and socioeconomic factors in 1980 (childhood) and 2011 (adulthood); and polygenic cognitive potential was calculated based on genome-wide association studies. RESULTS: We found that nonrational thinking, polygenic cognitive potential, cognitive performance, or socioeconomic factors were not related to social intolerance. Regarding cognitive styles, low flexibility (B = -0.759, p \u3c .001), high perseverance (B = 1.245, p \u3c .001), and low persistence (B = -0.329, p \u3c .001) predicted higher social intolerance consistently in the analyses. DISCUSSION: When developing prejudice-reduction interventions, it should be considered that educational level or cognitive performance may not be crucial for development of social intolerance. Adopting certain cognitive styles may play more important roles in development of social intolerance

Does social intolerance vary according to cognitive styles, genetic cognitive capacity, or education?

Background Low education, low cognitive abilities, and certain cognitive styles are suggested to predispose to social intolerance and prejudices. Evidence is, however, restricted by comparatively small samples, neglect of confounding variables and genetic factors, and a narrow focus on a single sort of prejudice. We investigated the relationships of education, polygenic cognitive potential, cognitive performance, and cognitive styles with social intolerance in adulthood over a 15-year follow-up. Methods We used data from the prospective population-based Young Finns Study (n = 960-1679). Social intolerance was evaluated with the Social Intolerance Scale in 1997, 2001, and 2011; cognitive performance with the Cambridge Neuropsychological Test Automated Battery in 2011; cognitive styles in 1997; and socioeconomic factors in 1980 (childhood) and 2011 (adulthood); and polygenic cognitive potential was calculated based on genome-wide association studies. Results We found that nonrational thinking, polygenic cognitive potential, cognitive performance, or socioeconomic factors were not related to social intolerance. Regarding cognitive styles, low flexibility (B = -0.759, p < .001), high perseverance (B = 1.245, p < .001), and low persistence (B = -0.329, p < .001) predicted higher social intolerance consistently in the analyses. Discussion When developing prejudice-reduction interventions, it should be considered that educational level or cognitive performance may not be crucial for development of social intolerance. Adopting certain cognitive styles may play more important roles in development of social intolerance.Peer reviewe

First genome-wide association study on rocuronium dose requirements shows association with SLCO1A2

Background: Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10-25%) and bile ( 70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation. Methods: One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50-100 mg kg(-1) min(-1)) and remifentanil (0.05-0.25 mg kg(-1) min(-1)). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0-10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further. Results: The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P Conclusions: Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.Peer reviewe

Genetic analyses implicate complex links between adult testosterone levels and health and disease

BackgroundTestosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of genetically determined testosterone on complex diseases in both sexes.MethodsLeveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality.ResultsWe show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes.ConclusionsOverall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences.Plain language summaryHormones, such as testosterone, travel around the body communicating between the different parts. Testosterone is present at higher levels in men, but also present in women. Variable testosterone levels explain some differences in human traits and disease prevalence. Here, we study how adult testosterone levels relate to health and disease. Genetic, i.e. inherited, differences in testosterone levels contribute to many traits specific to men or women, such as women's reproductive health, hormonal cancers, and hair growth typical in males. However, testosterone levels do not appear as a major cause of most traits studied, including psychiatric diseases and metabolic health. Normal variation in baseline testosterone levels thus seems to have a relatively minor impact on health and disease.Leinonen et al. investigate correlations between testosterone levels and disease using genetic and health registry data from the UK Biobank and FinnGen. There is a lack of evidence for normal variation in testosterone levels having a causal contribution to most non-sex-specific traits.Peer reviewe

Differences in psychosocial functioning between psychotic disorders in the Finnish SUPER study

Background: Psychotic disorders differ in their impact on psychosocial functioning. However, few studies have directly compared psychosocial functioning and its determinants between schizophrenia, schizoaffective disorder (SAD), bipolar disorder (BD), and major depressive disorder with psychotic features (psychotic MDD). Objective: We compared rates of independent living, employment, marriage, and having children between these diagnostic groups in a large national sample of participants with psychotic disorders in Finland. Methods: A cross-sectional substudy of participants (N = 9148) aged 18 to 65 years in the Finnish SUPER study, recruited nationwide from health-and social care settings and with advertisements. Psychosis diagnoses, age of onset, and hospitalizations were collected from healthcare registers. Participants were interviewed for psychosocial functioning. Associations of age of onset, hospitalizations, gender, and education with psychosocial functioning were analyzed using logistic regression models. Results: Of participants, 13.8% were employed or studying, 72.0% living independently and 32.5% had children. Overall, BD was associated with best, SAD and psychotic MDD with intermediate, and schizophrenia with worst level of psychosocial functioning. Greatest differences were found in independent living (OR 4.06 for BD vs. schizophrenia). In multivariate models, gender and number of hospitalizations predicted employment, marriage, and independent living in all diagnostic categories, and age of onset in some diagnostic categories. Conclusions: Level of functioning and psychosocial outcomes differed markedly between psychotic disorders, particularly in independent living. Outcomes were worst for schizophrenia and best for BD. Across all psychotic disorders, female gender and lifetime number of hospitalizations had strong independent associations with marriage, employment, and independent living.Peer reviewe

Does social intolerance vary according to cognitive styles, genetic cognitive capacity, or education?

BackgroundLow education, low cognitive abilities, and certain cognitive styles are suggested to predispose to social intolerance and prejudices. Evidence is, however, restricted by comparatively small samples, neglect of confounding variables and genetic factors, and a narrow focus on a single sort of prejudice. We investigated the relationships of education, polygenic cognitive potential, cognitive performance, and cognitive styles with social intolerance in adulthood over a 15-year follow-up.MethodsWe used data from the prospective population-based Young Finns Study (n = 960‒1679). Social intolerance was evaluated with the Social Intolerance Scale in 1997, 2001, and 2011; cognitive performance with the Cambridge Neuropsychological Test Automated Battery in 2011; cognitive styles in 1997; and socioeconomic factors in 1980 (childhood) and 2011 (adulthood); and polygenic cognitive potential was calculated based on genome-wide association studies.ResultsWe found that nonrational thinking, polygenic cognitive potential, cognitive performance, or socioeconomic factors were not related to social intolerance. Regarding cognitive styles, low flexibility (B = –0.759, p B = 1.245, p B = –0.329, p DiscussionWhen developing prejudice-reduction interventions, it should be considered that educational level or cognitive performance may not be crucial for development of social intolerance. Adopting certain cognitive styles may play more important roles in development of social intolerance.</p

Circulating inflammatory cytokines and risk of five cancers : a Mendelian randomization analysis

Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.Peer reviewe

The relationship between temperament, polygenic score for intelligence and cognition : A population-based study of middle-aged adults

We investigated whether temperament modifies an association between polygenic intelligence potential and cognitive test performance in midlife. The participants (n = 1647, born between 1962 and 1977) were derived from the Young Finns Study. Temperament was assessed with Temperament and Character Inventory over a 15-year follow-up (1997, 2001, 2007, 2012). Polygenic intelligence potential was assessed with a polygenic score for intelligence. Cognitive performance (visual memory, reaction time, sustained attention, spatial working memory) was assessed with CANTAB in midlife. The PGSI was significantly associated with the overall cognitive performance and performance in visual memory, sustained attention and working memory tests but not reaction time test. Temperament did not correlate with polygenic score for intelligence and did not modify an association between the polygenic score and cognitive performance, either. High persistence was associated with higher visual memory (B = 0.092; FDR-adj. p = 0.007) and low harm avoidance with higher overall cognitive performance, specifically better reaction time (B = -0.102; FDR-adj; p = 0.007). The subscales of harm avoidance had different associations with cognitive performance: higher "anticipatory worry," higher "fatigability," and lower "shyness with strangers" were associated with lower cognitive performance, while the role of "fear of uncertainty" was subtest-related. In conclusion, temperament does not help or hinder one from realizing their genetic potential for intelligence. The overall modest relationships between temperament and cognitive performance advise caution if utilizing temperament-related information e.g. in working-life recruitments. Cognitive abilities may be influenced by temperament variables, such as the drive for achievement and anxiety about test performance, but they involve distinct systems of learning and memory.Peer reviewe

Circulating metabolites and the risk of type 2 diabetes : a prospective study of 11,896 young adults from four Finnish cohorts

Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.Peer reviewe