Browsing by Subject "genetic"

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  • Quitt, Pia R.; Bruehschwein, Andreas; Matiasek, Kaspar; Wielaender, Franziska; Karkamo, Veera; Hytonen, Marjo K.; Meyer-Lindenberg, Andrea; Dengler, Berett; Leeb, Tosso; Lohi, Hannes; Fischer, Andrea (2021)
    Background Shaking puppy syndrome is commonly attributed to abnormal myelination of the central nervous system. Hypothesis/Objectives To report the long-term clinical course and the imaging characteristics of hypomyelinating leukodystrophy in German Shepherd dogs. Animals and Methods Three related litters with 11 affected dogs. Results The 11 affected dogs experienced coarse, side-to-side tremors of the head and trunk, which interfered with normal goal-oriented movements and disappeared at rest. Signs were noticed shortly after birth. Nine dogs were euthanized, 3 dogs underwent pathological examination, and 2 littermates were raised by their breeder. Tremors improved gradually until 6 to 7 months of age. Adult dogs walked with severe residual pelvic limb ataxia. One dog developed epilepsy with tonic-clonic seizures at 15 months of age. Conventional magnetic resonance imaging (MRI) disclosed homogenous hyperintense signal of the entire subcortical white matter in 3 affected 7-week-old dogs and a hypointense signal in a presumably unaffected littermate. Subcortical white matter appeared isointense to gray matter at 15 and 27 weeks of age on repeated MRI. Abnormal white matter signal with failure to display normal gray-white matter contrast persisted into adulthood. Cerebellar arbor vitae was not visible at any time point. Clinical signs, MRI findings, and pathological examinations were indicative of a hypomyelinating leukodystrophy. All parents of the affected litters shared a common ancestor and relatedness of the puppies suggested an autosomal recessive mode of inheritance. Conclusion We describe a novel hypomyelinating leukodystrophy in German Shepherd dogs with a suspected inherited origin.
  • Virtanen, Suvi (Helsingin yliopisto, 2017)
    There has been a steady increase in alcohol consumption in Finland since the 1969 law reform, which allowed convenience stores to sell mild alcoholic beverages such as beer. Since then, the yearly consumption has increased from 3.6 liters in 1968 to 10.8 liters of pure alcohol per capita in 2016. Increasing levels of alcohol use tend to produce high economic and population health costs. Understanding why changes in alcohol consumption behavior occur enables development of more efficient prevention and intervention programs. Alcohol consumption is not distributed equally across the population. Liberalization of Finnish alcohol policy and culture from the 1960s onwards made alcohol more available than ever before, and especially the post-war cohorts started to use significantly more alcohol than the generations before them. Evidently, there are between-individual differences in alcohol use in addition to group level differences. According to decades of research, approximately 50% of the variation between individuals in alcohol consumption can be explained by genetic sources. In other words, the heritability of alcohol use is 50%, while non-genetic factors explain the other half. However, heritability is not a static estimate, but can be modified by social forces. While it has been established that the younger generations consume significantly more alcohol than generations preceding them, only a few studies to date have examined whether the importance of genetic influences on alcohol consumption is dependent on birth cohort or generation. The current study examined, if social control during a specific time in history (e.g. how strict is alcohol policy and the cultural climate while a generation is growing up) can affect the heritability of alcohol use in later life. Mean level differences in alcohol consumption quantity and abstinence trajectories of birth cohorts were also estimated. The older Finnish twin cohort data consists of all Finnish same-sex twin pairs born before 1958 with both co-twins alive in 1975 (n = 24 481). The data were collected in four waves in 1975, 1981, 1990, and 2011. Age of the participants at study baseline in 1975 ranged from 18 to 95. Participants were grouped into seven 10-year cohorts based on their birth year. Mean trajectories of alcohol consumption quantity and abstinence over the life course were estimated for men and women separately with hierarchical growth curve models. Cohort effects and age-by-cohort interactions were also investigated. The heritability of alcohol consumption and abstinence was estimated using structural equation modelling. Birth cohort effects on heritability of alcohol use were examined by comparing heritability estimates of different cohorts at similar ages. Mean levels of alcohol consumption quantity were the highest in the youngest birth cohorts. Women drank less than men in all cohorts. The decline in the quantity of monthly alcohol use due to aging was relatively small, and appeared to be more prominent in the older birth cohorts. The odds of abstaining became lower in every successive birth cohort. Moreover, women were more likely to be abstinent than men. The aging effect of increasing abstinence was notable only in the oldest birth cohorts. Birth cohort differences in the heritability of alcohol consumption quantity were found: heritability was 25% (CI 12–38%) in the older generation (born 1901–1920) and 48% (CI 39–50%) in the younger generation (born 1941–1957) of men at the age of 54–74. For women, heritability was 60% in the older and younger generation. In alcohol abstinence, a single model was run for men and women. The shared environmental component explained a large proportion of the variation in the older generation (43%), whereas unique environment (54%) and additive genetic influences (40%) were more important among the younger generation. The findings from the present study suggest that social control during a specific time in history may have a long-term impact on alcohol consumption behavior (i.e. how and why alcohol is used) of an entire generation growing up during that period.
  • Virtanen, Suvi; Kuja-Halkola, Ralf; Mataix-Cols, David; Jayaram-Lindström, Nitya; D'Onofrio, Brian M.; Larsson, Henrik; Ruck, Christian; Suvisaari, Jaana; Lichtenstein, Paul; Latvala, Antti (2020)
    Background Causes of the comorbidity of substance misuse with anxiety-related and depressive disorders (anxiety/depression) remain poorly known. We estimated associations of substance misuse and anxiety/depression in the general population and tested them while accounting for genetic and shared environmental factors. Methods We studied individuals born in Sweden 1968–1997 (n = 2 996 398) with follow-up in nationwide register data for 1997–2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Substance misuse was defined as ICD-10 alcohol or drug use disorder or an alcohol/drug-related criminal conviction. Three dimensions of ICD-10 anxiety and depressive disorders and a substance misuse dimension were identified through exploratory factor analysis. Results Substance misuse was associated with a 4.5-fold (95% CI 4.50–4.58) elevated risk of lifetime generalized anxiety/depression, 4.7-fold (95% CI 4.63–4.82) elevated risk of panic disorder and agora/social phobia, and 2.9-fold elevated risk of phobias/OCD (95% CI 2.82–3.02) as compared to those without substance misuse. The associations were attenuated in within-family analyses but we found elevated risks in monozygotic twin pairs discordant for substance misuse as well as significant non-shared environmental correlations. The association between anxiety/depression and substance misuse was mainly driven by generalized anxiety/depression, whereas other anxiety/depression dimensions had minor or no independent associations with substance misuse. Conclusions Substance misuse and anxiety/depression are associated at the population level, and these associations are partially explained by familial liabilities. Our findings indicate a common genetic etiology but are also compatible with a potential partially causal relationship between substance misuse and anxiety/depression.
  • Haisma, Sjoukje-Marije; Weersma, Rinse K.; Joosse, Maria E.; de Koning, Barbara A. E.; de Meij, Tim; Koot, Bart G. P.; Wolters, Victorien; Norbruis, Obbe; Daly, Mark J.; Stevens, Christine; Xavier, Ramnik J.; Koskela, Jukka; Rivas, Manuel A.; Visschedijk, Marijn C.; Verkade, Henkjan J.; Barbieri, Ruggero; Jansen, Dianne B. H.; Festen, Eleonora A. M.; van Rheenen, Patrick F.; van Diemen, Cleo C. (2021)
    BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole-exome sequencing (WES) has contributed to understanding the molecular basis of very early-onset IBD, but rare protein-altering genetic variants have not been identified for early-onset PSC. We performed WES in patients diagnosed with PSC METHODS In this multicentre study, WES was performed on 87 DNA samples from 29 patient-parent trios with early-onset PSC. We selected rare (minor allele frequency <2%) coding and splice-site variants that matched recessive (homozygous and compound heterozygous variants) and dominant (de novo) inheritance in the index patients. Variant pathogenicity was predicted by an in-house developed algorithm (GAVIN), and PSC-relevant variants were selected using gene expression data and gene function. RESULTS In 22 of 29 trios we identified at least 1 possibly pathogenic variant. We prioritized 36 genes, harbouring a total of 54 variants with predicted pathogenic effects. In 18 genes, we identified 36 compound heterozygous variants, whereas in the other 18 genes we identified 18 de novo variants. Twelve of 36 candidate risk genes are known to play a role in transmembrane transport, adaptive and innate immunity, and epithelial barrier function. CONCLUSIONS The 36 candidate genes for early-onset PSC need further verification in other patient cohorts and evaluation of gene function before a causal role can be attributed to its variants.
  • FinnGen Rheumatology Clinical Expe; Palomaki, Antti; Palotie, Aarno; Koskela, Jukka; Eklund, Kari K.; Pirinen, Matti; Ripatti, Samuli; Laitinen, Tarja; Mars, Nina (2021)
    Objectives To estimate lifetime risk of developing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with respect to the strongest known risk factor for pulmonary fibrosis, a MUC5B promoter variant. Methods FinnGen is a collection of epidemiological cohorts and hospital biobank samples, integrating genetic data with up to 50 years of follow-up within nationwide registries in Finland. Patients with RA and ILD were identified from the Finnish national hospital discharge, medication reimbursement and cause-of-death registries. We estimated lifetime risks of ILD by age 80 with respect to the common variant rs35705950, a MUC5B promoter variant. Results Out of 293 972 individuals, 1965 (0.7%) developed ILD by age 80. Among all individuals in the dataset, MUC5B increased the risk of ILD with a HR of 2.44 (95% CI: 2.22 to 2.68). Out of 6869 patients diagnosed with RA, 247 (3.6%) developed ILD. In patients with RA, MUC5B was a strong risk factor of ILD with a HR similar to the full dataset (HR: 2.27, 95% CI: 1.75 to 2.95). In patients with RA, lifetime risks of ILD were 16.8% (95% CI: 13.1% to 20.2%) for MUC5B carriers and 6.1% (95% CI: 5.0% to 7.2%) for MUC5B non-carriers. The difference between risks started to emerge at age 65, with a higher risk among men. Conclusion Our findings provide estimates of lifetime risk of RA-ILD based on MUC5B mutation carrier status, demonstrating the potential of genomics for risk stratification of RA-ILD.
  • Tölli, Pekka; Keltikangas-Järvinen, Liisa; Lehtimäki, Terho; Ravaja, Niklas; Hintsanen, Mirka; Ahola-Olli, Ari; Pahkala, Katja; Kähönen, Mika; Hutri-Kähönen, Nina; Laitinen, Tomi T.; Tossavainen, Päivi; Taittonen, Leena; Dobewall, Henrik; Jokinen, Eero; Raitakari, Olli; Cloninger, C. Robert; Rovio, Suvi; Saarinen, Aino (2022)
    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.