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AbstractWe have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.

The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.118.002115 ; BACKGROUND: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms. METHODS: We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression. RESULTS: A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10-6 after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood. CONCLUSIONS: Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics. ; Dr van der Laan is funded through grants from the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS I&II]) and the Interuniversity Cardiology Institute of the Netherlands (ICIN, 09.001). Drs van der Laan and Haitjema are both funded through the FP7 EU project CVgenes@target (HEALTH-F2-2013–601456). Dr Siemelink is funded by the European Union (BiomarCaRE, grant number: HEALTH-2011–278913), and the technology foundation Stichting voor de Technische Wetenschappen through the Danone partnership program (Project 11679). The UCL Hospitals NIHR Biomedical Research Centre and the Dutch Heart Foundation (Junior Staff Member 2014T001) supported by Dr Asselbergs. The BiKE study was conducted with support from the Swedish Heart and Lung Foundation, the Swedish Research Council (K2009-65X-2233-01-3, K2013-65X-06816-30-4, and 349-2007-8703), Uppdrag Besegra Stroke (P581/2011–123), the Strategic Cardiovascular Programs of Karolinska Institutet and Stockholm County Council, the Stockholm County Council (ALF2011-0260 and ALF-2011-0279), the Foundation for Strategic Research and the European Commission (CarTarDis). ; Peer-reviewed ; Publisher Version

Ye-Jin Lee,1 SeungHo Choi,2 Sung-Youn Kwon,2 Yunhwan Lee,2 Jung Kyu Lee,3 Eun Young Heo,3 Hee Soon Chung,3,4 Deog Kyeom Kim3,4 1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 2Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 135-984 Korea; 3Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea; 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Boramae-Gil 41, Dongjak-gu, Seoul 156-707, Republic of KoreaTel +82-2-870-3207Fax +82-2-831-0714Email kimdkmd@gmail.comBackground: Identifying the genetic basis of airflow limitation is one of the most interesting issues for understanding chronic obstructive pulmonary disease (COPD) pathophysiology. Several studies have shown that some genetic variants associated with COPD have been identified in genome-wide association study (GWAS), especially in patients with moderate to severe COPD; genetic susceptibility for airflow limitation in the early COPD phase has not been widely studied.Objective: We investigated the genetic variants in early COPD.Methods: The present study analyzed Gene-environment interaction and phenotype (GENIE) cohort that included participants who received health screening examination. The association between single nucleotide polymorphism (SNP) and susceptibility to early COPD (FEV1 predicted ≥ 50% and FEV1/FVC < 0.7) was tested.Results: A total of 130 patients with early COPD and 3478 controls (1700 ever smokers and 1778 never smokers) were recruited. When compared with the total controls, certain SNPs (rs2818103, rs875033, rs9354627, rs34552148) on chromosome 6 were included at the top of our list (p= 5.6 × 10– 7 ∼ 9.6 × 10– 6) although they did not reach genome-wide significance. When compared with the never smoker controls, two SNPs (rs2857210, rs2621419) of the HLA-DQB2 gene class were persistently associated with susceptibility to early COPD.Conclusion: Certain SNPs located on chromosome 6 or the HLA-DQB2 gene were the top-scoring SNPs for the association with susceptibility to early COPD in the Korean GENIE cohort.Keywords: early chronic obstructive pulmonary disease, genome-wide association study, single nucleotide polymorphism, SNP, HLA-DQ gene

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene. ; This work was supported by RO1 CA154823, the Lustgarten Foundation, and federal funds from the NCI, US NIH under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, and mention of trade names, commercial products, or organizations does not imply endorsement by the US government. Geno-typing Services were provided by the CIDR and the NCIs CGR. CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University, contract number HHSN268201100011I. The IARC/Central Europe study was supported by a grant from the US NCI at the NIH (R03 CA123546-02) and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, and MH CZ- DRO-MMCI 00209805). The work at Johns Hopkins University was supported by the NCI Grants P50CA062924 and R01CA97075. Additional support was provided by, Susan Wojcicki, and Dennis Troper, and the Sol Goldman Pancreas Cancer Research Center. The Mayo Clinic Biospecimen Resource for Pancreas Research study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). The Memorial Sloan Ket- tering Cancer Center Pancreatic Tumor Registry is supported by P30CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family, Foundation, and the Society of MSKCC. The PACIFIC Study was supported by RO1CA102765, Kaiser Permanente, and Group Health Cooperative. The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; Grant number 442302). R.E.N. is supported by a NHMRC Senior Research Fellowship (#1060183). The UCSF pancreas study was supported by NIH-NCI grants (R01CA1009767, R01CA109767-S1, and R0CA059706) and the Joan Rombauer Pancreatic Cancer Fund. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting pro- gram; the NCIs SEER Program under contract HSN261201000140C awarded to CPIC; and the CDCs National Program of Cancer Registries, under agreement #U58DP003862-01 awarded to the California Department of Public Health. The Yale (CT) pancreas cancer study is supported by NCI at the U.S. NIH, grant 5R01CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. Studies included in PAN- DoRA were partly funded by the Czech Science Foundation (No. P301/12/1734), the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Baden- Württemberg State Ministry of Research, Science and Arts (Professor H. Brenner), the Heidelberger EPZ-Pancobank (Professor M.W. Büchler and team: Professor T. Hackert, Dr. N. A. Giese, Dr. Ch. Tjaden, E. Soyka, M. Meinhardt; Heidelberger. Stiftung Chir- urgie and BMBF grant 01GS08114), the BMBH (Professor P. Schirmacher; BMBF grant 01EY1101), the " 5 × 1000 " voluntary contribution of the Italian Government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54, and RC1303GA50), the Italian Association for Research on Cancer (Professor A. Scarpa; AIRC n. 12182), the Italian Ministry of Research (Professor A. Scarpa; FIRB - RBAP10AHJB), the Italian FIMP-Ministry of Health (Professor A. Scarpa; 12 CUP_J33G13000210001), and by the National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, UK. We would like to acknowledge the contribution of Dr. Frederike Dijk and Professor Oliver Busch (Academic Medical Center, Amsterdam, the Netherlands). Assistance with genotype data quality control was provided by Cecelia Laurie and Cathy Laurie at the University of Washington Genetic Analysis Center. The American Cancer Society (ACS) funds the creation, maintenance, and updating of the Cancer Prevention Study II cohort. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://phpa.dhmh.maryland.gov/ cancer , 410-767-4055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data. We thank all the CLUE participants. The Melbourne Col- laborative Cohort Study (MCCS) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414 and by the infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The NYU study (AZJ and AAA) was funded by NIH R01 CA098661, UM1 CA182934 and center grants P30 CA016087 and P30 ES000260. The PANKRAS II Study in Spain was supported by research grants from Instituto de Salud Carlos III-FEDER, Spain: Fondo de Investigaciones Sanitarias (FIS; #PI13/00082 and #PI15/01573) and Red Temática de Investigación Cooperativa en Cáncer, Spain (#RD12/ 0036/0050); and European Cooperation in Science and Technology (COST Action #BM1204: EU_Pancreas), Ministerio de Ciencia y Tecnología (CICYT SAF 2000-0097), Fondo de Investigación Sanitaria (95/0017), Madrid, Spain; Generalitat de Catalunya(CIRIT—SGR);"Red temática de investigación cooperativa de centros en Cáncer (C03/10),"Red temática de investigación cooperativa de centros en Epidemiología y salud pública(C03/09), and CIBER de Epidemiología (CIBERESP), Madrid. The Physicians 'Health Study was supported by research grants CA-097193, CA-34944, CA-40360, HL- 26490, and HL-34595 from the NIH, Bethesda, MD, USA. The Womens Health Study was supported by research grants CA-047988, HL-043851, HL-080467, and HL-099355 from the NIH, Bethesda, MD, USA. Health Professionals Follow-up Study is supported by NIH grant UM1 CA167552 from the NCI, Bethesda, MD, USA. Nurses ' Health Study is supported by NIH grants UM1 CA186107, P01 CA87969, and R01 CA49449 from the NCI, Bethesda, MD, USA. Additional support from the Hale Center for Pancreatic Cancer Research, U01 CA21017 from the NCI, Bethesda, MD, USA, and the United States Department of Defense CA130288, Lustgarten Foundation, Pancreatic Cancer Action Network, Noble Effort Fund, Peter R. Leavitt Family Fund, Wexler Family Fund, and Promises for Purple to B.M. Wolpin is acknowledged. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf . We thank Laurie Burdett, Aurelie Vogt, BelyndaHicks, Amy Hutchinson, Meredith Yeager, and other staff at the NCI's Division ofEpidemiology and Genetics (DECG) CGR for GWAS genotyping. We also thank Bao Tran, Jyoti Shetty, and other members of the NCI Center for Cancer Research (CCR) Sequencing Facility for sequencing RNA from histologically normal pancreatic tissue samples (LTG samples). This study utilized the high-performance computational cap- abilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA (http://biowulf.nih.gov). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the pancreatic tissue data from the GTEx Portal on 05/04/17. The results published here are in part based upon data generated by The Cancer Genome Atlas (TCGA) managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov/. We acknowledge the clinical contributors that provided PDAC samples and the data producers of RNA-seq and GWAS genotype data from TCGA Research Network. The data set used for the analyses described in this manuscript was obtained by formal permission through the TCGA Data Access Committee (DAC) ; Sí

Obesity is a complex phenotype affected by genetic and environmental influences such as sociocultural factors and individual behaviors. Previously, we performed two separate genome-wide investigations for adiposity-related traits (BMI, percentage body fat (), abdominal circumference (ABDCIR), and serum leptin and serum adiponectin levels) in families from American Samoa and in families from Samoa. The two polities have a common evolutionary history but have lately been influenced by variations in economic development, leading to differences in income and wealth and in dietary and physical activity patterns. We now present a genome-wide linkage scan of the combined samples from the two polities. We adjust for environmental covariates, including polity of residence, education, cigarette smoking, and farm work, and use variance component methods to calculate univariate and bivariate multipoint lod scores. We identified a region on 9p22 with genome-wide significant linkage for the bivariate phenotypes ABDCIR– (1-d.f. lod 3.30) and BMI– (1-d.f. lod 3.31) and two regions with genome-wide suggestive linkage on 8p12 and 16q23 for adiponectin (lod 2.74) and the bivariate phenotype leptin–ABDCIR (1-d.f. lod 3.17), respectively. These three regions have previously been reported to be linked to adiposity-related phenotypes in independent studies. However, the differences in results between this study and our previous polity-specific studies suggest that environmental effects are of different importance in the samples. These results strongly encourage further genetic studies of adiposity-related phenotypes where extended sets of carefully measured environmental factors are taken into account.

This work was supported by Fondo de Investigacion Sanitaria of the Instituto de Salud Carlos III(Spain) grant 08/0744 and by RETICS Program RD08/0075 that are partially financed by the European Regional Development Fund of the European Union, and by grants from the Xunta de Galicia and BMBF KN Rheuma (C2.12 to TW). ; Alonso-Perez, E., Suarez-Gestal, M., Calaza, M., Sebastiani, G.D., Pullmann, R., Papasteriades, C., Kovacs, A., Skopouli, F.N., Bijl, M., Suarez, A., Marchini, M., Migliaresi, S., Carreira, P., Ordi-Ros, J., Witte, T., Ruzickova, S., Santos, M.J., Barizzone, N., Blanco, F.J., Lauwerys, B.R., Gomez-Reino, J.J., Gonzalez, A.

This work was supported by grants 08/0744 and 11/01048 and by RETICS Program, RD08/0075 (RIER) of the Instituto de Salud Carlos III (Spain) that are partially financed by the European Regional Development Fund of the European Union, and by grants from the Xunta de Galicia and by DFG KFO 250, TP 03 to TW. ; Alonso-Perez, E., Suarez-Gestal, M., Calaza, M., Ordi-Ros, J., Balada, E., Bijl, M., Papasteriades, C., Carreira, P., Skopouli, F.N., Witte, T., Endreffy, E., Marchini, M., Migliaresi, S., Sebastiani, G.D., Santos, M.J., Suarez, A., Blanco, F.J., Barizzone, N., Pullmann, R., Ruzickova, S., Lauwerys, B.R., Gomez-Reino, J.J., Gonzalez, A., Liz, M., Schmidt, R.E., Kappou-Rigatou, I., Scorza, R., Kovacs, A., Balada, E., Kallenberg, C.G., Vinagre, F., Dostal, C., Pullmann Jr., R., Mavromati, M., D'Alfonso, S., Gutierrez, C., Rego, I.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n = 93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n = 98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record. ; In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.Molecular Psychiatry advance online publication, 20 June 2017; doi:10.1038/mp.2017.120. ; The recruitments and assessments and subjects in the discovery data set were funded by the Dutch Ministry of Defence, and the DNA methylation and mRNA analyses of discovery data set were funded by the VENI Award fellowship from the Netherlands Organisation for Scientific Research (NWO, grant number 916.11.086) to BPFR. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and VU University Amsterdam. The Marine Resilience Study was funded by the United States Department of Veterans Affairs Health Service Research and Development project SDR 09-0128, the Marine Corps, and the Navy Bureau of Medicine and Surgery (to DGB) and NIH 1 R01MH093500 (to CN).

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.