Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 10 × 10-773 and 6.7 × 10-5. This now allows prioritization of the gene of interest for subsequent functional studies.</p

Lymph node metastases in breast cancer : investigating associations with tumor characteristics, molecular subtypes, and polygenic risk score using a continuous growth model

DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author on request, after ethical approvals have been obtained from the Swedish ethical review board. Funding information: Cancerfonden, Grant/Award Number: 2020/0716; Vetenskapsrådet, Grant/Award Number: 2020-01302Peer reviewedPublisher PD

Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Acknowledgements: The computations and data handling were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, Uppsala University, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. This research has been conducted using the UK Biobank Resource under Application Number 22224. Funding: Open Access funding provided by Karolinska Institute. Open Access funding provided by Karolinska Institute. This work was financed by the Swedish Research Council (Grant 2018-02547, 2015-03255, 2019-01272, 2018-02077), the Swedish Cancer Society (Grants CAN 2016/684), the Stockholm County Council (Grant no. 20170088), the Karolinska Institutet’s Research Foundation (Grant 2018-02146), Karolinska Institutet’s Strategic Research Program in Epidemiology, King Gustaf V:s and Queen Victoria's Foundation of Freemasons, and the Åke Wibergs Foundation (M19-0294). FG was a Leopoldina Postdoctoral Fellow (Grant no. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. Correction to: Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance (Human Genetics, (2020), 10.1007/s00439-020-02249-w) The data were exclusively retrieved from the UK Biobank and can be accessed upon request from the UK Biobank. The mitochondrial DNA abundance as computed in this manuscript will be reported back to the UK Biobank upon publication. The scripts to compute the weights and the weighted mtDNA abundance in the UKB dataset will be published at https://github.com/GrassmannLab/MT_UKB.Peer reviewedPublisher PD

Interval breast cancer is associated with other types of tumors

Contributions: F.G. and K.C. conceived and designed the project; K.C. acted as the principal investigator; P.H., M.E, M.G., Women’s Health Initiative organized patient recruitment and sample collection; F.G. and W.H. analyzed the data; W.H., M.G., P.H., K.C. contributed to data interpretation; F.G. and K.C. wrote the manuscript with input from all authors. All authors approved of the final manuscript. Acknowledgements: This work was financed by the Swedish Research Council (Grant 2018-02547), the Swedish Cancer Society (grants CAN 2016/684 and 2013/469), the Cancer Society in Stockholm (Grant 141092), the Stockholm County Council (Grant No. LS 1211–1594), and the Karolinska Institutet’s Research Foundation (Grant 2018-02146). The KARMA study is supported by the Märit and Hans Rausing Initiative Against Breast Cancer and the Cancer and Risk Prediction Center (CRisP), a Linnaeus center (grant 70867902) financed by the Swedish Research Council. F.G. was a Leopoldina Postdoctoral Fellow (Grant No. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. W.H. was supported by the Swedish Research Council for Health, Working Life and Welfare (FORTE, 2018-00877). We thank Dr. Johanna Holm for her valuable contribution to the manuscript. Genotyping of the OncoArray was principally funded by three sources: the PERSPECTIVE project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec, and the Quebec Breast Cancer Foundation; the National Cancer Institute Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) projects (National Institutes of Health [NIH] grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program; and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combination of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA148065 (DRIVE, part of the GAME-ON initiative). All studies and funders are listed in ref. 60. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed, and/or approved by the WHI, and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. The study sponsors had no role in the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Open access funding provided by Karolinska InstitutePeer reviewedPublisher PD

Mammographic features are associated with cardiometabolic disease risk and mortality

Open Access via the OUP Open Access Agreement Acknowledgements: The authors thank all the participants in the KARMA study and personnel for their devoted work during data collection. They also would like to acknowledge Jose ́ Tapia for helping in data management. Funding: This work was supported by “Ma ̈rit and Hans Rausing’s Initiative Against Breast Cancer” and was financed by the Swedish Research Council (Grant 2018-02547 to K.C.), the Swedish Cancer Society (Grant 19 0266 and 19 0267 to K.C.), FORTE (Grant 2016-00081 to K.C.), and the Karolinska Institutet’s Research Foundation (Grant 2018-02146 to F.G.). F.G. was a Leopoldina Postdoctoral Fellow (Grant No. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. H.Y. was supported by Start-up Fund for high-level talents of Fujian Medical University (Grant .No. XRCZX2020007) and Start-up Fund for Scientific Research, Fujian Medical University (Grant No. 2019QH1002). The funding agency had no role in the study design, data collection, analyses, and data interoperation, in writing the manuscript, or in the decision to submit the manuscript for publication.Peer reviewedPublisher PD

Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD)

Funding This research was funded by the Deutsche Forschungsgemeinschaft (GR5065/1-1) and institutional funds (Titel 77). Acknowledgments All contributing sites and additional funding information for the IAMDGC data are acknowledged in this publication: Fritsche et al. (2016) Nature Genetics 48 134–143, (doi:10.1038/ng.3448); The International AMD Genomics consortium’s web page is: http://eaglep.case.edu/iamdgc_web/, and additional information is available on: http://csg.sph.umich.edu/abecasis/public/amd2015/. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; Schaefer and Risch, PIs) awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Northern California Community Benefit Programs. The RPGEH and the Resource for Genetic Epidemiology Research in Adult Health and Aging are described in the following publication, Schaefer C, et al., The Kaiser Permanente Research Program on Genes, Environment and Health: Development of a Research Resource in a Multi-Ethnic Health Plan with Electronic Medical Records, In preparation, 2013. This research has been conducted using the UK Biobank Resource under Application Number 44862. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101825, & MH101820), the University of North Carolina—Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810), and to the University of Pennsylvania (MH101822). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v8.p2.Peer reviewedPublisher PD

The association of single nucleotide polymorphisms (SNPs) with breast density and breast cancer survival : the Malmö Diet and Cancer Study

The author(s) received the following financial support for the research, authorship, and/or publication of this article: This work is supported by government funding for clinical research within the National Health Services, Sweden. FG was a Leopoldina Postdoctoral Fellow (Grant No. LPDS 2018-06) funded by the Academy of Sciences Leopoldina.Peer reviewedPublisher PD

Seed sequence polymorphism rs2168518 and allele-specific target gene regulation of hsa-miR-4513

Acknowledgements We thank Lisa Michaelis and Dr Karolina Plößl (Institute of Human Genetics, University of Regensburg) for excellent technical help and thorough proofreading of the manuscript, respectively. We thank Marina Sauer and Franz-Stephan Attenkofer (Institute of Human Genetics, University of Regensburg) for their support in generating the luciferase reporter vectors. Conflict of Interest statement. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Funding German Research Foundation (GR5065/1-1 to F.G.); and the Helmut Ecker Foundation (Ingolstadt, Germany) (no. 05/17 to B.H.F.W).Peer reviewedPublisher PD

The agonistic TSPO ligand XBD173 attenuates the glial response thereby protecting inner retinal neurons in a murine model of retinal ischemia

Peer reviewedPublisher PD

Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD)

Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association of rs2168518 with AMD but also with other complex phenotypes by using large independent datasets from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. We then performed a functional annotation with reference to gene expression regulation based on data from the Genotype-Tissue Expression (GTEx) project and RegulomeDB. Association analysis revealed a gender-specific association with male AMD patients and an association predominantly with choroidal neovascularization. Further, the AMD association colocalizes with an association signal of several blood pressure-related phenotypes and with the gene expression regulation of CYP1A1, a member of the cytochrome P450 superfamily of monooxygenases. Functional annotation revealed altered transcription factor (TF) binding sites for gender-specific TFs, including SOX9 and SRY. In conclusion, the pleiotropic 15q24.1 association signal suggests a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1