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  • Sung, Yun J.; Winkler, Thomas W.; de las Fuentes, Lisa; Bentley, Amy R.; Brown, Michael R.; Kraja, Aldi T.; Schwander, Karen; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K.; Li, Changwei; Feitosa, Mary F.; Kilpelainen, Tuomas O.; Richard, Melissa A.; Noordam, Raymond; Aslibekyan, Stella; Aschard, Hugues; Bartz, Traci M.; Dorajoo, Rajkumar; Liu, Yongmei; Manning, Alisa K.; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M.; Tayo, Bamidele O.; Warren, Helen R.; Zhao, Wei; Zhou, Yanhua; Matoba, Nana; Sofer, Tamar; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Giulianini, Franco; Goel, Anuj; Harris, Sarah E.; Heikkinen, Sami; Koistinen, Heikki A.; Weir, David R. (2018)
    Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p <5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p <5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).
  • Virtanen, Suvi; Kaprio, Jaakko; Viken, Richard; Rose, Richard J.; Latvala, Antti (2019)
    Aims To estimate birth cohort effects on alcohol consumption and abstinence in Finland and to test differences between birth cohorts in genetic and environmental sources of variation in Finnish adult alcohol use. Design The Older Finnish Twin Cohort longitudinal survey study 1975-2011. Setting Finland. Participants A total of 26 121 same-sex twins aged 18-95 years (full twin pairs at baseline n = 11 608). Measurements Outcome variables were the quantity of alcohol consumption (g/month) and abstinence (drinking zero g/month). Predictor variables were 10-year birth cohort categories and socio-demographic covariates. In quantitative genetic models, two larger cohorts (born 1901-20 and 1945-57) were compared. Findings Multi-level models in both sexes indicated higher levels of alcohol consumption in more recent birth cohorts and lower levels in earlier cohorts, compared with twins born 1921-30 (all P < 0.003). Similarly, compared with twins born 1921-30, abstaining was more common in earlier and less common in more recent cohorts (all P < 0.05), with the exception of men born 1911-20. Birth cohort differences in the genetic and environmental variance components in alcohol consumption were found: heritability was 21% [95% confidence interval (CI) = 0-56%] in the earlier-born cohort of women [mean age 62.8, standard deviation (SD) = 5.3] and 51% (95% CI = 36-56%) in a more recent cohort (mean age 60.2, SD = 3.7) at the age of 54-74. For men, heritability was 39% (95% CI = 27-45%) in both cohorts. In alcohol abstinence, environmental influences shared between co-twins explained a large proportion of variation in the earlier-born cohort (43%, 95% CI = 23-63%), whereas non-shared environmental (54%, 95% CI = 39-72%) and additive genetic influences (40%, 95% CI = 13-61%) were more important among more recent cohorts of men and women. Conclusion The contribution of genetic and environmental variability to variability in alcohol consumption in the Finnish population appears to vary by birth cohort.
  • CIMBA Grp; Silvestri, Valentina; Leslie, Goska; Barnes, Daniel R.; Aittomäki, Kristiina; Nevanlinna, Heli (2020)
    Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P <.001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P <.001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P <.001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P <.001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. Conclusions and Relevance Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs. This cohort study compares the cancer spectrum and frequencies between male BRCA1 and BRCA2 pathogenic variant carriers. Question Are there cancer phenotype differences between male BRCA1 and BRCA2 pathogenic variant carriers? Findings In this cohort study of 6902 men with a BRCA1 or BRCA2 pathogenic variant, being affected by cancer, particularly breast, prostate, and pancreatic cancers and developing multiple primary tumors, was associated with a higher probability for a man of being a BRCA2, rather than a BRCA1, pathogenic variant carrier. Meaning Surveillance programs in men with BRCA1 and BRCA2 pathogenic variants should be tailored in light of these gene-specific cancer phenotype differences. These results may inform the design of prospective studies on cancer risks in male BRCA1 and BRCA2 pathogenic variant carriers.
  • Putkinen, Vesa; Saarikivi, Katri (2018)
    Musical training has been associated with superior performance in various executive function tasks. To date, only a few neuroimaging studies have investigated the neural substrates of the supposed "musician advantage" in executive functions, precluding definite conclusions about its neural basis. Here, we provide a selective review of neuroimaging studies on plasticity and typical maturation of executive functions, with the aim of investigating how proficient performance in executive function tasks is reflected in brain activity. Specifically, we examine the evidence for the hypothesis that enhanced or mature executive functions are manifested as efficient use of neural systems supporting those functions. We also present preliminary results from a functional magnetic resonance imaging study suggesting-in line with this hypothesis-that musically trained adolescents recruit frontoparietal regions less strongly during executive functions tasks than untrained peers.