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Objective To test the hypothesis that age-related macular degeneration (AMD) and retinal microvascular signs are differentially associated with lobar and deep cerebral microbleeds (CMBs). Methods CMBs in lobar regions indicate cerebral amyloid angiopathy (CAA). β-Amyloid deposits are implicated in both CAA and AMD. Deep CMBs are associated with hypertension, a major risk factor for retinal microvascular damage. This population-based cohort study included 2,502 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who undertook binocular digital retinal photographs at baseline (2002–2006) to assess retinal microvascular signs and AMD and brain MRI scan at both baseline and follow-up (2007–2011) to assess CMBs. We assessed retinal microvascular lesion burden by counting the 3 retinal microvascular signs (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) concurrently present in the participant. We used multiple logistic models to examine the association of baseline retinal pathology to incident CMBs detected at follow-up. Results During an average 5.2 years of follow-up, 461 people (18.3%) developed new CMBs, including 293 in exclusively lobar regions and 168 in deep regions. Pure geographic atrophy was significantly associated with strictly lobar CMBs (multivariable-adjusted odds ratio 2.59, 95% confidence interval [CI] 1.01–6.65) but not with deep CMBs. Concurrently having ≥2 retinal microvascular signs was associated with a 3-fold (95% CI 1.73–5.20) increased likelihood for deep CMBs but not exclusively lobar CMBs. Conclusions Retinal microvascular signs and pure geographic atrophy may be associated with deep and exclusively lobar CMBs, respectively, in older people. These results have implications for further research to define the role of small vessel disease in cognitive impairment. ; The AGES-Reykjavik Study was funded by the NIH (contract N01-AG-12100); the Intramural Research Program of the National Institute on Aging and the National Eye Institute (ZIAEY000401), NIH; and the Icelandic Heart Association and the Icelandic Parliament. None of the funding organizations or sponsors were involved in study design; in the collection, analysis, or interpretation of data; in writing of the report; or in the decision to submit the manuscript for publication. ; Peer Reviewed

Publisher's version (útgefin grein) ; Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk. ; We want to thank Susanne Sauer and Maik Ködel for their technical assistance and Jessica Keverne for language editing. We thank all mothers who took part in the on-going PREDO study. We are grateful to all the families in Norway who participate in the on-going MoBa cohort study. We thank the Drakenstein Child Health Study staff, and the clinical and administrative staff of the Western Cape Government Department of Health at Paarl Hospital and at the clinics for support of the Study. We also thank our collaborators and students. Finally, we thank all mothers and children enroled in the Drakenstein Child Health Study. We thank the research participants and employees of 23andMe, Inc. for their contribution to this study. This work was supported by the Academy of Finland (E.K., H.L., K.R., and J.L.); University of Helsinki Research Funds (J.L., M.L.P., and H.L.), British Heart Foundation (RMR); Tommy's (RMR); European Commission (EK, KR, Horizon 2020 Award SC1–2016-RTD-733280 RECAP); NorFace DIAL (E.K., KR PremLife); Foundation for Pediatric Research (E.K.); Juho Vainio Foundation (E.K.); Novo Nordisk Foundation (E.K.); Signe and Ane Gyllenberg Foundation (E.K., K.R.); Sigrid Jusélius Foundation (E.K.); Finnish Medical Foundation (H.L.); Jane and Aatos Erkko Foundation (H.L.); Päivikki and Sakari Sohlberg Foundation (H.L., P.M.V.); the Clinical Graduate school in Pediatrics and Obstetrics/Gynaecology in University of Helsinki (P.M.V.). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537–06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (grant no 221097). This work was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. The Drakenstein Child Health Study is supported by the Bill and Melinda Gates Foundation (OPP 1017641); with additional support for this work from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD) under Award Number R21HD085849; and the Fogarty International Center (FIC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support for H.J.Z., D.J.S. and N.K., and for research reported in this publication was by the South African Medical Research Council (SAMRC); N.K. receives support from the SAMRC under a Self-Initiated Research Grant. The views and opinions expressed are those of the authors and do not necessarily represent the official views of the SAMRC. This work was also funded by the German Federal Ministry of Education and Research through the Research Consortium Integrated Network IntegraMent (grant 01ZX1314H) under the auspices of the e:Med Programme (NSM). The UCI cohort was supported by a European Research Area Network (ERA Net) Neuron grant (01EW1407A, CB) and National Institutes of Health grant (R01 HD-060628, CB) as well as NIH grant R01 MH-105538 (PDW). This work was also funded by the Canadian Institute for Advanced Research, Child and Brain Development Program, Toronto, ON, Canada (KJOD). ; Peer Reviewed

To find sequence variants affecting prostate cancer (PCA) susceptibility in an unscreened Romanian population we use a genome‐wide association study (GWAS). The study population included 990 unrelated pathologically confirmed PCA cases and 1034 male controls. DNA was genotyped using Illumina SNP arrays, and 24.295.558 variants were imputed using the 1000 Genomes data set. An association test was performed between the imputed markers and PCA. A systematic literature review for variants associated with PCA risk identified 115 unique variants that were tested in the Romanian sample set. Thirty of the previously reported SNPs replicated (P‐value < 0.05), with the strongest associations observed at: 8q24.21, 11q13.3, 6q25.3, 5p15.33, 22q13.2, 17q12 and 3q13.2. The replicated variants showing the most significant association in Romania are rs1016343 at 8q24.21 (P = 2.2 × 10−4), rs7929962 at 11q13.3 (P = 2.7 × 10−4) and rs9364554 at 6q25.2 (P = 4.7 × 10−4). None of the variants tested in the Romanian GWAS reached genome‐wide significance (P‐value <5 × 10−8) but 807 markers had P‐values <1 × 10−4. Here, we report the results of the first GWAS of PCA performed in a Romanian population. Our study provides evidence that a substantial fraction of previously validated PCA variants associate with risk in this unscreened Romanian population. ; This study was funded in part by the European Union FP7 Program (ProMark project 202059) and by the EEA grant (ROMCAN project RO14-0017; EEAJRPRO-NO-20131-10191). ; Peer Reviewed