Functional Polymorphisms in Oxytocin and Dopamine Pathway Genes and the Development of Dispositional Compassion Over Time : The Young Finns Study

Background: We define compassion as an enduring disposition that centers upon empathetic concern for another person's suffering and the motivation to act to alleviate it. The contribution of specific candidate genes to the development of dispositional compassion for others is currently unknown. We examine candidate genes in the oxytocin and dopamine signaling pathways. Methods: In a 32-year follow-up of the Young Finns Study (N = 2,130, 44.0% men), we examined with multiple indicators latent growth curve modeling the molecular genetic underpinnings of dispositional compassion for others across the life span. We selected five single nucleotide polymorphisms (SNPs) whose functions are known in humans: rs2268498 (OXTR), rs3796863 (CD38) (related to lower oxytocin levels), rs1800497 (ANKK1/DRD2), rs4680 (COMT), and rs1611115 (DBH) (related to higher dopamine levels). Compassion was measured with Cloninger's Temperament and Character Inventory on three repeated observations spanning 15 years (1997-2012). Differences between gender were tested. Results: We did not find an effect of the five SNPs in oxytocin and dopamine pathway genes on the initial levels of dispositional compassion for others. Individuals who carry one or two copies of the T-allele of DBH rs1611115, however, tend to increase faster in compassion over time than those homozygotes for the C-allele, b = 0.063 (SE = 0.027; p = 0.018). This effect was largely driven by male participants, 0.206 (SE = 0.046; p <0.001), and was not significant in female participants when analyzed separately. Conclusions: Men who are known to have, on average, lower compassion than women seem to reduce this difference over time if they carry the T-allele of DBH rs1611115. The direction of the association indicates that dopamine signaling activity rather than overall dopamine levels might drive the development of compassion.Peer reviewe

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

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Genetic differential susceptibility to the parent-child relationship quality and the life span development of compassion

The development of compassion for others might be influenced by the social experiences made during childhood and has a genetic component. No research has yet investigated whether the parent-child relationship quality interacts with genetic variation in the oxytocin and dopamine systems in predicting compassion over the life span. In the prospective Young Finns Study (N = 2099, 43.9% men), we examined the interaction between mother-reported emotional warmth and intolerance toward their child assessed in 1980 (age of participants, 3-18 years) and two established genetic risk scores for oxytocin levels and dopamine signaling activity. Dispositional compassion for others was measured with the Temperament and Character Inventory 1997, 2001, and 2012 (age of participants, 20-50 years). We found a gene-environment interaction (p = .031) that remained marginally significant after adjustment for multiple testing. In line with the differential susceptibility hypothesis, only participants who carry alleles associated with low dopamine signaling activity had higher levels of compassion when growing up with emotionally warm parents, whereas they had lower levels of compassion when their parents were emotionally cold. Children's genetic variability in the dopamine system might result in plasticity to early environmental influences that have a long-lasting effect on the development of compassion. However, our findings need replication.Peer reviewe

Magical thinking in individuals with high polygenic risk for schizophrenia but no non-affective psychoses-a general population study

A strong genetic background for psychoses is well-established. Most individuals with a high genetic risk for schizophrenia, however, do not develop the disorder. We investigated whether individuals, who have a high genetic risk for schizophrenia but no non-affective psychotic disorders, are predisposed to develop milder forms of deviant thinking in terms of magical thinking. Participants came from the population-based Young Finns Study (n = 1292). The polygenic risk score for schizophrenia (PRS) was calculated on the basis of the most recent genome-wide association study (GWAS). Psychiatric diagnoses over the lifespan were collected up to 2017 from the registry of hospital care. Magical thinking was evaluated with the Spiritual Acceptance Scale (e.g., beliefs in telepathy, miracles, mystical events, or sixth sense) of the Temperament and Character Inventory in 1997, 2001, and 2012 (participants were 20-50-year-olds). We found that, among those who did not develop non-affective psychotic disorders, high PRS predicted higher magical thinking in adulthood (p = 0.001). Further, PRS predicted different developmental courses: a low PRS predicted a steady decrease in magical thinking from age 20 to 50 years, while in individuals with high PRS the decrease in magical thinking ceased in middle age so that their level of magical thinking remained higher than expected for that age. These findings remained when controlling for sex, childhood family environment, and adulthood socioeconomic factors. In conclusion, if high PRS does not lead to a non-affective psychotic disorder, it predicts milder forms of deviant thinking such as elevated magical thinking in adulthood, especially in middle age. The finding enhances our understanding of different outcomes of high genetic psychosis risk.Peer reviewe

The prognostic significance of T-wave inversion according to ECG lead group during long-term follow-up in the general population

Background Inverted T waves in the electrocardiogram (ECG) have been associated with coronary heart disease (CHD) and mortality. The pathophysiology and prognostic significance of T-wave inversion may differ between different anatomical lead groups, but scientific data related to this issue is scarce. Methods A representative sample of Finnish subjects (n = 6,354) aged over 30 years underwent a health examination including a 12-lead ECG in the Health 2000 survey. ECGs with T-wave inversions were divided into three anatomical lead groups (anterior, lateral, and inferior) and were compared to ECGs with no pathological T-wave inversions in multivariable-adjusted Fine-Gray and Cox regression hazard models using CHD and mortality as endpoints. Results The follow-up for both CHD and mortality lasted approximately fifteen years (median value with interquartile ranges between 14.9 and 15.3). In multivariate-adjusted models, anterior and lateral (but not inferior) T-wave inversions associated with increased risk of CHD (HR: 2.37 [95% confidence interval 1.20-4.68] and 1.65 [1.27-2.15], respectively). In multivariable analyses, only lateral T-wave inversions associated with increased risk of mortality in the entire study population (HR 1.51 [1.26-1.81]) as well as among individuals with no CHD at baseline (HR 1.59 [1.29-1.96]). Conclusions The prognostic information of inverted T waves differs between anatomical lead groups. T-wave inversion in the anterior and lateral lead groups is independently associated with the risk of CHD, and lateral T-wave inversion is also associated with increased risk of mortality. Inverted T wave in the inferior lead group proved to be a benign phenomenon.Peer reviewe

Long-term prognostic significance of the ST level and ST slope in the 12-lead ECG in the general population

Background: Even minor ST depression in the electrocardiogram (ECG) is associated with cardiovascular disease and increased mortality. There is limited data on the prognostic significance of ST-level changes in the general population. Subjects and methods: A random sample of Finnish subjects (n = 6354) aged over 30 years (56.1% women) underwent a health examination including a 12-lead ECG in the Health 2000 survey. The effects of relative ST level as a continuous variable and ST slope (upsloping, horizontal, downsloping) in three different lead groups were analyzed using a multi-adjusted Cox proportional hazard model separately for men and women with total mortality as endpoint. Results: The follow-up lasted for 13.7 (SD 3.3) years for men and 13.9 (SD 3.1) years for women. Lower lateral ST levels were associated with all-cause mortality in multi-adjusted models in both genders (at.) + 80 ms hazard ratio [HR] 0.64 for a change of 1.0 mm [95% confidence interval 0.49-0.84, p = 0.002] for men and HR 0.61 [0.48-0.78, p <0.001] for women). Associated coronary heart disease had no major influence on the results. Exclusion of subjects with ECG signs of left ventricular hypertrophy from the analyses increased the mortality risk of lower lateral ST levels in men but decreased it in women. For the anterior and inferior lead groups, no statistically significant difference was seen after multivariate adjustment. ST slope was not an independent predictor of mortality after multivariate adjustment Conclusion: Lower ST level in the lateral ECG leads is an independent prognostic factor to predict all-cause mortality in the general population. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Pro-opiomelanocortin and its Processing Enzymes Associate with Plaque Stability in Human Atherosclerosis -Tampere Vascular Study

alpha-melanocyte-stimulating hormone (alpha-MSH) is processed from pro-opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. alpha-MSH also promotes macrophage reverse cholesterol transport by inducing ATP-binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and alpha-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. alpha-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating alpha-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque alpha-MSH levels. Second, immunohistochemical analyses revealed the presence of alpha-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of alpha-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, alpha-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of alpha-MSH might protect against atherosclerosis

Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression : a population-based mtDNA sequencing study

The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i. e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex-and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control

RNA-sequencing reveals that STRN, ZNF484 and WNK1 add to the value of mitochondrial MT-COI and COX10 as markers of unstable coronary artery disease

Markers in monocytes, precursors of macrophages, which are related to CAD, are largely unknown. Therefore, we aimed to identify genes in monocytes predictive of a new ischemic event in patients with CAD and/or discriminate between stable CAD and acute coronary syndrome. We included 66 patients with stable CAD, of which 24 developed a new ischemic event, and 19 patients with ACS. Circulating CD14+ monocytes were isolated with magnetic beads. RNA sequencing analysis in monocytes of patients with (n = 13) versus without (n = 11) ischemic event at follow-up and in patients with ACS (n = 12) was validated with qPCR (n = 85). MT-COI, STRN and COX10 predicted new ischemic events in CAD patients (power for separation at 1% error rate of 0.97, 0.90 and 0.77 respectively). Low MT-COI and high STRN were also related to shorter time between blood sampling and event. COX10 and ZNF484 together with MT-COI, STRN and WNK1 separated ACS completely from stable CAD patients. RNA expressions in monocytes of MT-COI, COX10, STRN, WNK1 and ZNF484 were independent of cholesterol lowering and antiplatelet treatment. They were independent of troponin T, a marker of myocardial injury. But, COX10 and ZNF484 in human plaques correlated to plaque markers of M1 macrophage polarization, reflecting vascular injury. Expression of MT-COI, COX10, STRN and WNK1, but not that of ZNF484, PBMCs paired with that in monocytes. The prospective study of relation of MT-COI, COX10, STRN, WNK1 and ZNF484 with unstable CAD is warranted