Self-Reported Cognitive Functions Predict the Trajectory of Paranoid Ideation Over a 15-Year Prospective Follow-Up

Background This study investigated whether self-reported cognitive functions (i.e. task orientation, distractibility, persistence, flexibility, and perseverance) predict the trajectory of paranoid ideation over a 15-year prospective follow-up in adulthood. Methods The participants came from the population-based Young Finns study (N = 1210-1213). Paranoid ideation was assessed with the Paranoid Ideation Scale of the Symptom Checklist-90 Revised (SCL-90R) in 1997, 2001, 2007, and 2012. Self-reported cognitive functions were evaluated in 1997 with the Task orientation, Distractibility, Persistence, and Flexibility scales of the DOTS-R (the Revised Dimensions of Temperament Survey) and the Perseverance scale of the FCB-TI (the Formal Characteristics of Behaviour - Temperament Inventory). The data was analyzed using growth curve models that were adjusted for age, sex, and socioeconomic factors in childhood and adulthood. Results Low self-reported task orientation, low persistence, high distractibility, low flexibility, and high perseverance predicted higher level of paranoid ideation over the 15-year follow-up. Conclusions Self-reported cognitive functions seem to predict paranoid ideation over a long-term follow-up. Promoting cognitive functions in early interventions may have long-term protective influences against the development of paranoid ideation in non-clinical populations.Peer reviewe

High Risk Population Isolate Reveals Low Frequency Variants Predisposing to Intracranial Aneurysms

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.Public Library of Science open acces

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

Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health RegistersPublic Library of Science open acces

Temporal variability of serum miR-191, miR-223, miR-128, and miR-24 in multiple sclerosis : A 4-year follow-up study

Background: Circulating microRNAs (miRNA) are suggested to be a promising biomarker for multiple sclerosis (MS). Previously, miR-128-3p, miR-24-3p, miR-191-5p and miR-223-3p have been reported to associate with MS pathology. However, their longitudinal changes and association with the disease activity have not been studied. Objectives: To evaluate the serum temporal variability of miR-128-3p, miR-191-5p, miR-24-3p, and miR-223-3p and their association with disability and disease activity in MS. Methods: The expression of four miRNAs in serum was studied in 57 MS patients, 18 clinically isolated syndrome patients, and 32 healthy controls over the four-year follow-up. Results: At the baseline, miR-191-5p was overexpressed in RRMS in comparison to controls, and its levels correlated positively with EDSS and progression index (PI) in RRMS. Increased levels of miR-128-3p were detected in PPMS in comparison to controls, and increased levels correlated with EDSS and PI in RRMS. The expression of miR-24-3p and miR-223-3p did not differ between the subtypes, but miR-223-3p correlated negatively with T1 lesions volumes in SPMS and PPMS. Over the four-years follow-up period, the expression of miR-128-3p and miR-24-3p was stable longitudinally, while temporal changes of miR-191-5p and miR-223-3p were observed in MS. Temporal changes in miR-191-5p were observed to be associated with an increase of EDSS or MRI activity, while the variability of miR-223-3p was associated with relapses. Conclusion: Temporal variability of miR-191-5p and miR-223-3p are associated with changes in disability accumulation and disease activity. While, miR-128-3p was stably expressed and associated with the PPMS subtype and correlated with disability accumulation.publishedVersionPeer reviewe

Does high optimism protect against the inter-generational transmission of high BMI? The Cardiovascular Risk in Young Finns Study

Objective: The transmission of overweight from one generation to the next is well established, however little is known about what psychosocial factors may protect against this familial risk. The aim of this study was to examine whether optimism plays a role in the intergenerational transmission of obesity. Methods: Our sample included 1043 participants from the prospective Cardiovascular Risk in Young FINNS Study. Optimism was measured in early adulthood (2001) when the cohort was aged 24-39 years. BMI was measured in 2001 (baseline) and 2012 when they were aged 35-50 years. Parental BMI was measured in 1980. Hierarchical linear regression and logistic regression were used to examine the association between optimism and future BMI/obesity, and whether an interaction existed between optimism and parental BMI when predicting BMI/obesity 11 years later. Results: High optimism in young adulthood demonstrated a negative relationship with high BMI in mid-adulthood, but only in women (beta = - 0.127, p = 0.001). The optimism x maternal BMI interaction term was a significant predictor of future BMI in women (beta = 0.588, p = 0.036). The logistic regression results confirmed that high optimism predicted reduced obesity in women (OR = 0.68, 95% CI, 0.55-0.86), however the optimism x maternal obesity interaction term was not a significant predictor (OR = 0.50, 95% CI, 0.10-2.48). Conclusions: Our findings supported our hypothesis that high optimism mitigated the intergenerational transmission of high BMI, but only in women. These findings also provided evidence that positive psychosocial factors such as optimism are associated with long-term protective effects on BMI in women.Peer reviewe

C-reactive protein and temperament: An instrumental variable analysis

Cited by: 0; All Open Access, Gold Open Access, Green Open AccessPeer reviewe

Somatic complaints in early adulthood predict the developmental course of compassion into middle age

Objective: The aim of the present study was to investigate (i) whether somatic complaints predict the developmental course of compassion in adulthood, and (ii) whether this association depends on alexithymic features. Methods: The participants came from the population-based Young Finns study (N = 471-1037). Somatic complaints (headache, stomachache, chest pain, backache, fatigue, exhaustion, dizziness, heartburn, heartbeat, and tension) were evaluated with a self-rating questionnaire in 1986 when participants were aged between 18 and 24 years. Compassion was assessed with the Compassion Scale of the Temperament and Character Inventory (TCI) in 1997, 2001, and 2012. The data were analyzed using growth curve models. Results: We obtained a significant compassion-age interaction (B = -0.137, p =.02) and a compassion -age squared interaction (B = 0.007, p =.006), when predicting the course of somatic complaints. Specifically, in participants without frequent somatic complaints, compassion steadily increased with age in adulthood. In participants with frequent somatic complaints, however, compassion remained at a lower level until the age of 40 years, then started to increase, and achieved the normal level of compassion approximately at the age of 50 years. The association between somatic complaints and compassion over age was found to be independent of alexithymic features. The analyses were adjusted for a variety of covariates (age, gender, use of health care in childhood, depression in childhood, parental socioeconomic factors, parental care-giving practices, stressful life events, parental alcohol intoxication, and participants' socioeconomic factors in adulthood). Conclusion: Frequent somatic complaints may predict delayed development of compassion in adulthood. This association was found to be independent of alexithymic features.Peer reviewe