Publications by authors named "Felix Grassmann"

56 Publications

Interval breast cancer is associated with interferon immune response.

Eur J Cancer 2022 Jan 10;162:194-205. Epub 2022 Jan 10.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: The aggressive nature of breast cancers detected between planned mammographic screens, so-called interval cancers, remains elusive. Here, we aim to characterise underlying molecular features of interval cancer.

Methods: From 672 patients with invasive breast cancer, we analysed gene expression differences between 90 'true' interval cancer cases (i.e. women with low-dense breasts defined as per cent mammographic density <25%) and 310 screen-detected tumours while accounting for PAM50 subtypes and thus overall tumour aggressiveness. We computed an interval cancer gene expression profile (IC-Gx) in a total of 2270 breast tumours (regardless of interval cancer status) and tested for association with expression-based immune subtypes in breast cancer. In addition, we investigated the contribution of inherited and somatic genetic variants in distinct features of interval cancer.

Results: We identified 8331 genes nominally associated with interval cancer (P-value < 0.05, fold-change > 1.5). Gene set enrichment analysis showed immune-related pathways as key processes altered in interval cancer. Our IC-Gx, based on 47 genes with the strongest associations (false discovery rate < 0.05), was found to be associated mainly with immune subtypes involving interferon response. We isolated an interaction network of interval cancer and interferon genes for which a significant load of somatic and germline variants in class I interferon genes was observed.

Conclusion: We identified novel molecular features of interval breast cancer highlighting interferon pathways as a potential target for prevention or treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.12.003DOI Listing
January 2022

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

Hum Mol Genet 2021 Oct 4. Epub 2021 Oct 4.

Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.

MicroRNAs (miRNAs) are small post-transcriptional regulators that offer promising targets for treating complex diseases. To this end, hsa-miR-4513 is an excellent candidate as this gene harbors within its conserved heptametrical seed sequence a frequent polymorphism (rs2168518), which has previously been associated with several complex phenotypes. So far, little is known about the biological mechanism(s) underlying these associations. In an initial step, we now aimed to identify allele-specific target genes of hsa-miR-4513. We performed RNA sequencing in a miRNA overexpression model in human umbilical vein endothelial cells transfected with separated hsa-miR-4513 alleles at rs2168518, namely hsa-miR-4513-G and hsa-miR-4513-A. Genes specifically regulated by the rs2168518 alleles were independently verified by quantitative reverse transcription PCR (qRT-PCR), Western Blot analysis and allele-specific miRNA binding via a luciferase reporter assay. By a text-based search publicly available databases such as Online Mendelian Inheritance in Man and Mouse Genome Informatics were utilized to link target genes of hsa-miR-4513 to previously described phenotypes. Overall, we identified 23 allele-specific hsa-miR-4513 target genes and replicated 19 of those independently via qRT-PCR. Western Blot analysis and luciferase reporter assays conducted for an exemplary subsample further confirmed the allele-specific regulation of these genes by hsa-miR-4513. Remarkably, multiple allele-specific target genes identified are linked via text retrieval to several phenotypes previously reported to be associated with hsa-miR-4513. These genes offer promising candidates for ongoing research on the functional pathobiological impact of hsa-miR-4513 and its seed polymorphism rs2168518. This could give rise to therapeutic applications targeting this miRNA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab292DOI Listing
October 2021

Mammographic features are associated with cardiometabolic disease risk and mortality.

Eur Heart J 2021 09;42(34):3361-3370

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, Stockholm 171 65, Sweden.

Aims: In recent years, microcalcifications identified in routine mammograms were found to be associated with cardiometabolic disease in women. Here, we aimed to systematically evaluate the association of microcalcifications and other mammographic features with cardiometabolic disease risk and mortality in a large screening cohort and to understand a potential genetic contribution.

Methods And Results: This study included 57 867 women from a prospective mammographic screening cohort in Sweden (KARMA) and 49 583 sisters. Cardiometabolic disease diagnoses and mortality and medication were extracted by linkage to Swedish population registries with virtually no missing data. In the cardiometabolic phenome-wide association study, we found that a higher number of microcalcifications were associated with increased risk for multiple cardiometabolic diseases, particularly in women with pre-existing cardiometabolic diseases. In contrast, dense breasts were associated with a lower incidence of cardiometabolic diseases. Importantly, we observed similar associations in sisters of KARMA women, indicating a potential genetic overlap between mammographic features and cardiometabolic traits. Finally, we observed that the presence of microcalcifications was associated with increased cardiometabolic mortality in women with pre-existing cardiometabolic diseases (hazard ratio and 95% confidence interval: 1.79 [1.24-2.58], P = 0.002) while we did not find such effects in women without cardiometabolic diseases.

Conclusions: We found that mammographic features are associated with cardiometabolic risk and mortality. Our results strengthen the notion that a combination of mammographic features and other breast cancer risk factors could be a novel and affordable tool to assess cardiometabolic health in women attending mammographic screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423470PMC
September 2021

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

Int J Cancer 2021 09 21;149(6):1348-1357. Epub 2021 Jun 21.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

We investigate the association between rate of breast cancer lymph node spread and grade, estrogen receptor (ER) status, progesteron receptor status, decision tree derived PAM50 molecular subtype and a polygenic risk score (PRS), using data on 10 950 women included from two different data sources. Lymph node spread was analyzed using a novel continuous tumor progression model that adjusts for tumor volume in a biologically motivated way and that incorporates covariates of interest. Grades 2 and 3 tumors, respectively, were associated with 1.63 and 2.17 times faster rates of lymph node spread than Grade 1 tumors (P < 10 ). ER/PR negative breast cancer was associated with a 1.25/1.19 times faster spread than ER/PR positive breast cancer, respectively (P = .0011 and .0012). Among the molecular subtypes luminal A, luminal B, Her2-enriched and basal-like, Her2-enriched breast cancer was associated with 1.53 times faster spread than luminal A cancer (P = .00072). PRS was not associated with the rate of lymph node spread. Continuous growth models are useful for quantifying associations between lymph node spread and tumor characteristics. These may be useful for building realistic progression models for microsimulation studies used to design individualized screening programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33704DOI Listing
September 2021

Correction to: Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance.

Hum Genet 2021 Jun;140(6):863

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 65, Stockholm, Sweden.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-021-02258-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496643PMC
June 2021

Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance.

Hum Genet 2021 Jun 31;140(6):849-861. Epub 2020 Dec 31.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 65, Stockholm, Sweden.

Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that the abundance of mtDNA was significantly elevated in women compared to men, was negatively correlated with advanced age, higher smoking exposure, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and lower mortality. In addition, several biochemistry markers in blood-related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with mtDNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with mtDNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of mtDNA abundance to be around 8%. To investigate the consequence of altered mtDNA abundance, we performed a phenome-wide association study and found that mtDNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating mtDNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease-relevant processes, particularly those related to immunity and established mitochondrial functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02249-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099832PMC
June 2021

A systems genomics approach to uncover the molecular properties of cancer genes.

Sci Rep 2020 10 27;10(1):18392. Epub 2020 Oct 27.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 171 65, Stockholm, Sweden.

Genes involved in cancer are under constant evolutionary pressure, potentially resulting in diverse molecular properties. In this study, we explore 23 omic features from publicly available databases to define the molecular profile of different classes of cancer genes. Cancer genes were grouped according to mutational landscape (germline and somatically mutated genes), role in cancer initiation (cancer driver genes) or cancer survival (survival genes), as well as being implicated by genome-wide association studies (GWAS genes). For each gene, we also computed feature scores based on all omic features, effectively summarizing how closely a gene resembles cancer genes of the respective class. In general, cancer genes are longer, have a lower GC content, have more isoforms with shorter exons, are expressed in more tissues and have more transcription factor binding sites than non-cancer genes. We found that germline genes more closely resemble single tissue GWAS genes while somatic genes are more similar to pleiotropic cancer GWAS genes. As a proof-of-principle, we utilized aggregated feature scores to prioritize genes in breast cancer GWAS loci and found that top ranking genes were enriched in cancer related pathways. In conclusion, we have identified multiple omic features associated with different classes of cancer genes, which can assist prioritization of genes in cancer gene discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-75400-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591476PMC
October 2020

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

Cells 2020 10 8;9(10). Epub 2020 Oct 8.

Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.

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 , 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9102257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650707PMC
October 2020

A mega-analysis of expression quantitative trait loci in retinal tissue.

PLoS Genet 2020 09 1;16(9):e1008934. Epub 2020 Sep 1.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Significant association signals from genome-wide association studies (GWAS) point to genomic regions of interest. However, for most loci the causative genetic variant remains undefined. Determining expression quantitative trait loci (eQTL) in a disease relevant tissue is an excellent approach to zoom in on disease- or trait-associated association signals and hitherto on relevant disease mechanisms. To this end, we explored regulation of gene expression in healthy retina (n = 311) and generated the largest cis-eQTL data set available to date. Genotype- and RNA-Seq data underwent rigorous quality control protocols before FastQTL was applied to assess the influence of genetic markers on local (cis) gene expression. Our analysis identified 403,151 significant eQTL variants (eVariants) that regulate 3,007 genes (eGenes) (Q-Value < 0.05). A conditional analysis revealed 744 independent secondary eQTL signals for 598 of the 3,007 eGenes. Interestingly, 99,165 (24.71%) of all unique eVariants regulate the expression of more than one eGene. Filtering the dataset for eVariants regulating three or more eGenes revealed 96 potential regulatory clusters. Of these, 31 harbour 130 genes which are partially regulated by the same genetic signal. To correlate eQTL and association signals, GWAS data from twelve complex eye diseases or traits were included and resulted in identification of 80 eGenes with potential association. Remarkably, expression of 10 genes is regulated by eVariants associated with multiple eye diseases or traits. In conclusion, we generated a unique catalogue of gene expression regulation in healthy retinal tissue and applied this resource to identify potentially pleiotropic effects in highly prevalent human eye diseases. Our study provides an excellent basis to further explore mechanisms of various retinal disease etiologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462281PMC
September 2020

Association between breast cancer risk and disease aggressiveness: Characterizing underlying gene expression patterns.

Int J Cancer 2021 02 5;148(4):884-894. Epub 2020 Sep 5.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P < .05) including Ki-67 proliferation status (P < 5 × 10 ). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P < 5 × 10 ), HER2-enriched subtype (P < 5 × 10 ) and worse 10-year breast cancer-specific survival (log-rank P < 5 × 10 ). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818270PMC
February 2021

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.

BMC Med Genomics 2020 08 26;13(1):120. Epub 2020 Aug 26.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Background: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD.

Methods: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.

Results: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism).

Conclusions: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-020-00760-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449002PMC
August 2020

Hyperthyroidism is associated with breast cancer risk and mammographic and genetic risk predictors.

BMC Med 2020 08 25;18(1):225. Epub 2020 Aug 25.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177, Stockholm, Sweden.

Background: Despite the biological link between thyroid hormones and breast cancer cell proliferation shown in experimental studies, little is known about the association between hyperthyroidism and breast cancer, as well as its association with the most common mammographic and genetic risk predictors for breast cancer.

Methods: This study estimates the incidence rate ratios (IRRs) of breast cancer among women diagnosed with hyperthyroidism, compared to those who are not, using two cohorts: a Swedish national cohort of the general female population (n = 3,793,492, 2002-2011) and the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA, n = 69,598, 2002-2017). We used logistic regression to estimate the odds ratios (ORs) of hyperthyroidism according to the mammographic and genetic risk predictors for breast cancer.

Results: An increased risk of breast cancer was observed in patients in the national cohort with hyperthyroidism (IRR = 1.23, 95% CI = 1.12-1.36), particularly for toxic nodular goiter (IRR = 1.38, 95% CI = 1.16-1.63). Hyperthyroidism was associated with higher body mass index, early age at first birth, and lower breastfeeding duration. Higher mammographic density was observed in women with toxic nodular goiter, compared to women without hyperthyroidism. Additionally, among genotyped women without breast cancer in the KARMA cohort (N = 11,991), hyperthyroidism was associated with a high polygenic risk score (PRS) for breast cancer overall (OR = 1.98, 95% CI = 1.09-3.60) and for estrogen receptor-positive specific PRS (OR = 1.90, 95% CI = 1.04-3.43).

Conclusion: Hyperthyroidism is associated with an increased risk of breast cancer, particularly for patients with toxic nodular goiter. The association could be explained by higher mammographic density among these women, as well as pleiotropic genetic variants determining shared hormonal/endocrine factors leading to the pathology of both diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-020-01690-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446157PMC
August 2020

A Circulating MicroRNA Profile in a Laser-Induced Mouse Model of Choroidal Neovascularization.

Int J Mol Sci 2020 Apr 13;21(8). Epub 2020 Apr 13.

Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.

Choroidal neovascularization (CNV) is a pathological process in which aberrant blood vessels invade the subretinal space of the mammalian eye. It is a characteristic feature of the prevalent neovascular age-related macular degeneration (nAMD). Circulating microRNAs (cmiRNAs) are regarded as potentially valuable biomarkers for various age-related diseases, including nAMD. Here, we investigated cmiRNA expression in an established laser-induced CNV mouse model. Upon CNV induction in C57Bl/6 mice, blood-derived cmiRNAs were initially determined globally by RNA next generation sequencing, and the most strongly dysregulated cmiRNAs were independently replicated by quantitative reverse transcription PCR (RT-qPCR) in blood, retinal, and retinal pigment epithelium (RPE)/choroidal tissue. Our findings suggest that two miRNAs, mmu-mir-486a-5p and mmur-mir-92a-3p, are consistently dysregulated during CNV formation. Furthermore, in functional in vitro assays, a significant impact of mmu-mir-486a-5p and mmu-mir-92a-3p on murine microglial cell viability was observed, while mmu-mir-92a-3p also showed an impact on microglial mobility. Taken together, we report a robust dysregulation of two miRNAs in blood and RPE/choroid after laser-induced initiation of CNV lesions in mice, highlighting their potential role in pathology and eventual therapy of CNV-associated complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21082689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216141PMC
April 2020

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

Acta Radiol 2020 Oct 9;61(10):1326-1334. Epub 2020 Feb 9.

Diagnostic Radiology, Department of Translational Medicine, Skåne University Hospital, Lund University, Lund, Sweden.

Background: Genetic factors are important in determining breast density, and heritable factors account for 60% of the variation. Certain single nucleotide polymorphisms (SNPs) are associated with density and risk of breast cancer but the association with prognosis is not clear.

Purpose: To investigate associations between selected SNPs and breast cancer survival in the Malmö Diet and Cancer Study (MDCS).

Material And Methods: A total of 724 unrelated women with breast cancer and registered radiological and pathological data were identified in MDCS 1991-2007, with genotyping available for 672 women. Associations among 15 SNPs, density, and breast cancer-specific survival were analyzed using logistic/Cox regression, adjusted for factors affecting density and survival. Variants significantly associated with either density or survival were validated in a large independent breast cancer cohort (LIBRO-1).

Results: Minor homozygotes of SNPs rs9383589, and rs6557161, were associated with high breast density (adjusted odds ratio [AOR] 8.97, 95% confidence interval [CI] 1.35-59.57; AOR 2.08, 95% CI 1.19-3.65, respectively) and poorer breast cancer survival (adjusted hazard ratio [HR] 6.46, 95% CI 1.95-21.39; HR 2.30, 95% CI 1.33-3.96, respectively) compared to major homozygotes. For SNP rs3757318, , minor homozygotes (HR 7.46, 95% CI 2.28-24.45) were associated with poorer survival. We confirmed that rs6557161, was significantly associated with both density and survival in the LIBRO-1 study.

Conclusion: These findings support a shared genetic basis for density and breast cancer survival. The SNP significantly associated with both density and survival in both cohorts may be of interest in future research investigating polygenic risk scores for breast cancer risk and screening stratification purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0284185119900436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564305PMC
October 2020

CYP2D6 Genotype Predicts Tamoxifen Discontinuation and Prognosis in Patients With Breast Cancer.

J Clin Oncol 2020 02 4;38(6):548-557. Epub 2019 Dec 4.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Purpose: To examine the association between CYP2D6 genotype, discontinuation of tamoxifen therapy, and prognosis for breast cancer.

Patients And Methods: We conducted a prospective-retrospective study linking data from a clinical breast cancer register, the Swedish Prescribed Drug Register, and self-reported questionnaires. We genotyped CYP2D6 in 1,309 patients with breast cancer who were treated with tamoxifen and were diagnosed from 2005 to 2012; they were categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. We investigated whether metabolizer status was associated with tamoxifen discontinuation and prognosis for breast cancer using Cox regression analysis.

Results: The 6-month discontinuation rates of tamoxifen among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 7.1%, 7.6%, 6.7%, and 18.8%, respectively. A U-shaped association was found between CYP2D6 metabolizer status and breast cancer-specific mortality, with adjusted hazard ratios of 2.59 (95% CI, 1.01 to 6.67) for poor, 1.48 (95% CI, 0.72 to 3.05) for intermediate, 1 (reference) for normal, and 4.52 (95% CI, 1.42 to 14.37) for ultrarapid CYP2D6 metabolizers.

Conclusion: Both poor and ultrarapid CYP2D6 metabolizers of tamoxifen have a worse prognosis for breast cancer compared with normal metabolizers after receiving a standard dose of tamoxifen. This U-shaped association might call for individualized tamoxifen dosage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.01535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030887PMC
February 2020

Interval breast cancer is associated with other types of tumors.

Nat Commun 2019 10 22;10(1):4648. Epub 2019 Oct 22.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Breast cancer (BC) patients diagnosed between two screenings (interval cancers) are more likely than screen-detected patients to carry rare deleterious mutations in cancer genes potentially leading to increased risk for other non-breast cancer (non-BC) tumors. In this study, we include 14,846 women diagnosed with BC of which 1,772 are interval and 13,074 screen-detected. Compared to women with screen-detected cancers, interval breast cancer patients are more likely to have a non-BC tumor before (Odds ratio (OR): 1.43 [1.19-1.70], P = 9.4 x 10) and after (OR: 1.28 [1.14-1.44], P = 4.70 x 10) breast cancer diagnosis, are more likely to report a family history of non-BC tumors and have a lower genetic risk score based on common variants for non-BC tumors. In conclusion, interval breast cancer is associated with other tumors and common cancer variants are unlikely to be responsible for this association. These findings could have implications for future screening and prevention programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12652-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805891PMC
October 2019

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.

Ophthalmology 2020 02 16;127(2):186-195. Epub 2019 Jul 16.

Apellis Pharmaceuticals, Inc, Waltham, Massachusetts.

Purpose: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA.

Design: Prospective, multicenter, randomized, sham-controlled phase 2 study.

Participants: Two hundred forty-six patients with GA.

Methods: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging.

Main Outcome Measures: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events.

Results: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]).

Conclusions: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2019.07.011DOI Listing
February 2020

Cost-effective molecular inversion probe-based ABCA4 sequencing reveals deep-intronic variants in Stargardt disease.

Hum Mutat 2019 10 18;40(10):1749-1759. Epub 2019 Jun 18.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation-scanning methods. We aimed to develop a cost-effective sequencing method for ABCA4 exons and regions carrying known causal deep-intronic variants.

Methods: Fifty exons and 12 regions containing 14 deep-intronic variants of ABCA4 were sequenced using double-tiled single molecule Molecular Inversion Probe (smMIP)-based next-generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays.

Results: Thirty-four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep-intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep-intronic variant (c.4539+2065C>G) resulted in a 170-nt mRNA pseudoexon insertion (p.[Arg1514Lysfs*35,=]).

Conclusions: smMIPs-based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost-effective mutation detection in STGD1 cases in previously unsolved cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23787DOI Listing
October 2019

Insights into the loss of the Y chromosome with age in control individuals and in patients with age-related macular degeneration using genotyping microarray data.

Hum Genet 2020 Mar 27;139(3):401-407. Epub 2019 May 27.

Institut Jacques Monod, Université Paris Diderot, 15 rue Hélène Brion, 75013, Paris, France.

The extent of aneuploidy of the sex chromosomes increases with age in human leukocytes. Here, we re-explore the dynamics of normal loss of the Y chromosome (LOY) with age based on microarray data using two exponential models and two different ways to estimate the fraction of LOY. This analysis shows the existence of a significant correlation between the fraction of LOY estimated from molecular cytogenetics and genotyping microarray data. Although the specific estimates of the parameters for the two exponential models are different from those derived from cytogenetics data, the present analysis in an independent dataset of normal individuals confirms that X0 cells have a selective advantage over XY cells. Moreover, patients with age-related macular degeneration display higher fraction of LOY values and seem to have a predisposition to lose their Y chromosome even at young ages compared to control individuals. As there are no data available for the same individuals at different time points, the parameters reported here are average values drawn from population analyses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-019-02029-1DOI Listing
March 2020

Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

JAMA Ophthalmol 2019 Aug;137(8):867-876

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Importance: Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors.

Objective: To elucidate the contribution of common genetic variants to geographic atrophy lesion growth.

Design, Setting, And Participants: This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE).

Main Outcomes: The correlation between square root-transformed geographic atrophy growth rate and 7 596 219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times.

Main Outcomes And Measures: Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth.

Results: A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P = 4.09 × 10-8) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P = 4.07 × 10-7) as the most likely progression-associated genes.

Conclusions And Relevance: These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2019.1318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547131PMC
August 2019

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

J Neuroinflammation 2019 Feb 18;16(1):43. Epub 2019 Feb 18.

Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

Background: Ligand-driven modulation of the mitochondrial translocator protein 18 kDa (TSPO) was recently described to dampen the neuroinflammatory response of microglia in a retinal light damage model resulting in protective effects on photoreceptors. We characterized the effects of the TSPO ligand XBD173 in the postischemic retina focusing on changes in the response pattern of the major glial cell types of the retina-microglia and Müller cells.

Methods: Retinal ischemia was induced by increasing the intraocular pressure for 60 min followed by reperfusion of the tissue in mice. On retinal cell types enriched via immunomagnetic separation expression analysis of TSPO, its ligand diazepam-binding inhibitor (DBI) and markers of glial activation were performed at transcript and protein level using RNA sequencing, qRT-PCR, lipid chromatography-mass spectrometry, and immunofluorescent labeling. Data on cell morphology and numbers were assessed in retinal slice and flatmount preparations. The retinal functional integrity was determined by electroretinogram recordings.

Results: We demonstrate that TSPO is expressed by Müller cells, microglia, vascular cells, retinal pigment epithelium (RPE) of the healthy and postischemic retina, but only at low levels in retinal neurons. While an alleviated neurodegeneration upon XBD173 treatment was found in postischemic retinae as compared to vehicle controls, this neuroprotective effect of XBD173 is mediated putatively by its action on retinal glia. After transient ischemia, TSPO as a marker of activation was upregulated to similar levels in microglia as compared to their counterparts in healthy retinae irrespective of the treatment regimen. However, less microglia were found in XBD173-treated postischemic retinae at 3 days post-surgery (dps) which displayed a more ramified morphology than in retinae of vehicle-treated mice indicating a dampened microglia activation. Müller cells, the major retinal macroglia, show upregulation of the typical gliosis marker GFAP. Importantly, glutamine synthetase was more stably expressed in Müller glia of XBD173-treated postischemic retinae and homeostatic functions such as cellular volume regulation typically diminished in gliotic Müller cells remained functional.

Conclusions: In sum, our data imply that beneficial effects of XBD173 treatment on the postischemic survival of inner retinal neurons were primarily mediated by stabilizing neurosupportive functions of glial cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-019-1424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378755PMC
February 2019

Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides.

Genet Med 2019 08 15;21(8):1751-1760. Epub 2019 Jan 15.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.

Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.

Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.

Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0414-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752325PMC
August 2019

Conduct and Quality Control of Differential Gene Expression Analysis Using High-Throughput Transcriptome Sequencing (RNASeq).

Authors:
Felix Grassmann

Methods Mol Biol 2019 ;1834:29-43

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

High-throughput transcriptome sequencing (RNASeq) represents one of the most comprehensive and scalable methods to analyze global gene expression. It allows for absolute quantification of gene expression and also enables the discovery of novel transcripts and alternatively spliced isoforms. This chapter provides hand-on tools and a step-by-step procedure to analyze RNASeq data from punctures of two different retinal tissues (retina and RPE-choroid-sclera) at two different locations (periphery and macular region) from eight individuals. The procedure described in this chapter will use various programs from the free, open-source Tuxedo Suite software package to analyze sequencing data and to ascertain genes that are differentially expressed between retina and RPE-choroid-sclera.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-8669-9_2DOI Listing
April 2019

Y chromosome mosaicism is associated with age-related macular degeneration.

Eur J Hum Genet 2019 01 29;27(1):36-41. Epub 2018 Aug 29.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Age-related macular degeneration (AMD) is the leading cause of blindness in industrialised countries, and thereby a major individual but also a socio-economic burden. Y chromosome loss in nucleated blood cells has been implicated in age-related diseases such as Alzheimer disease and was shown to be caused by increasing age, smoking and genetic factors. Mosaic loss of Y chromosome (mLOY) in peripheral blood was estimated from normalised dosages of genotyping chip data covering the male-specific region of the Y chromosome. After quality control, we assessed the association of mLOY on AMD risk in 5772 male cases and 6732 male controls. In controls the prevalence of mLOY increased significantly with age, which is consistent with previous reports. Importantly, mLOY was associated with late-stage AMD with genome-wide significance (OR: 1.332 [95% CI: 1.206; 1.472], P = 1.60e-08), independent of age, the AMD genetic risk score and the first two principle components of ancestry. Additionally conditioning on smoking behaviour had no influence on the observed association strength. mLOY was strongest associated in individuals aged between 65 and 75 years. Taken together, mLOY is significantly associated with risk for AMD, independent of known and potential confounding factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-018-0238-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303255PMC
January 2019

Evaluation of serum sphingolipids and the influence of genetic risk factors in age-related macular degeneration.

PLoS One 2018 2;13(8):e0200739. Epub 2018 Aug 2.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Sphingolipids are bioactive molecules associated with oxidative stress, inflammation, and neurodegenerative diseases, but poorly studied in the context of age-related macular degeneration (AMD), a prevalent sight-threatening disease of the ageing retina. Here, we found higher serum levels of hexosylceramide (HexCer) d18:1/16:0 in patients with choroidal neovascularization (CNV) and geographic atrophy (GA), two manifestations of late stage AMD, and higher ceramide (Cer) d18:1/16:0 levels in GA patients. A sensitivity analysis of genetic variants known to be associated with late stage AMD showed that rs1061170 (p.Y402H) in the complement factor H (CFH) gene influences the association of Cer d18:1/16:0 with GA. To understand the possible influence of this genetic variant on ceramide levels, we established a cell-based assay to test the modulation of genes in the ceramide metabolism by factor H-like protein 1 (FHL-1), an alternative splicing variant of CFH that also harbors the 402 residue. We first showed that malondialdehyde-acetaldehyde adducts, an oxidation product commonly found in AMD retinas, induces an increase in ceramide levels in WERI-Rb1 cells in accordance with an increased expression of ceramide synthesis genes. Then, we observed that cells exposed to the non-risk FHL-1:Y402, but not the risk associated variant FHL-1:H402 or full-length CFH, downregulated ceramide synthase 2 and ceramide glucosyltransferase gene expression. Together, our findings show that serum ceramide and hexosylceramide species are altered in AMD patients and that ceramide levels may be influenced by AMD associated risk variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200739PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071970PMC
January 2019

Spectral Domain Optical Coherence Tomography Allows the Unification of Clinical Decision Making for the Evaluation of Choroidal Neovascularization Activity.

Ophthalmologica 2019 21;241(1):32-37. Epub 2018 Jun 21.

Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.

Purpose: This prospective observational clinical study investigated the benefits of spectral domain optical coherence tomography for specialists and residents in the management of neovascular age-related macular degeneration (AMD).

Procedures: The study involved 49 eyes of 44 patients. Patients were advised to present for reevaluation 4 weeks after the administration of the loading dose of vascular endothelial growth factor (VEGF)-inhibitors (3 intravitreal injections every 4 weeks after diagnosis). They were examined by residents (3-4 years' experience in ophthalmology) and specialists (> 5 years' experience). Each examiner evaluated the clinical situation and the spectral domain optical coherence tomography (SD-OCT) scan. After each evaluation, the examiners independently stated if further anti-VEGF treatment was recommended. The "true outcome" was defined as the specialist decision based on clinical evaluation and SD-OCT.

Results: Specialists and residents did not significantly differ in their accuracy in deciding on the correct treatment (p = 0.705 and p = 1), with or without the aid of SD-OCT. Both groups benefited from using SD-OCT to support their recommendations (p = 0.001 and p = 0.0002) and achieved a similar level of accuracy (p = 1 for difference).

Conclusions: Residents benefited more than specialists by using SD-OCT to substantiate their recommendation on how to manage exudative AMD after the administration of the loading dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000489344DOI Listing
February 2019

Pleiotropic Effects of Risk Factors in Age-Related Macular Degeneration and Seemingly Unrelated Complex Diseases.

Adv Exp Med Biol 2018 ;1074:247-255

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Age-related macular degeneration (AMD) is a complex disease with both environmental and genetic factors influencing disease risk. Genome-wide case-control association studies, candidate gene analyses, and epidemiological studies reinforced the notion that AMD is predominantly a disease of an impaired complement system and an altered high-density lipoprotein (HDL) metabolism. Recent reports demonstrated the pleiotropic role of the complement system and HDL in complex diseases such as cardiovascular disease, autoimmune disorders, cancer, and Alzheimer's disease. In light of these findings, we explore current evidence for a shared genetic and environmental risk of AMD and unrelated complex diseases based on epidemiological studies. Shared risk factors may indicate common pathways in disease pathology and thus may have implications for novel treatment options of AMD pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-319-75402-4_30DOI Listing
May 2019

Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H () gene family.

Proc Natl Acad Sci U S A 2018 05 23;115(19):E4433-E4442. Epub 2018 Apr 23.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195;

Structural variation and single-nucleotide variation of the complement factor H () gene family underlie several complex genetic diseases, including age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (AHUS). To understand its diversity and evolution, we performed high-quality sequencing of this ∼360-kbp locus in six primate lineages, including multiple human haplotypes. Comparative sequence analyses reveal two distinct periods of gene duplication leading to the emergence of four -related () gene paralogs ( and ∼25-35 Mya and and ∼7-13 Mya). Remarkably, all evolutionary breakpoints share a common ∼4.8-kbp segment corresponding to an ancestral gene promoter that has expanded independently throughout primate evolution. This segment is recurrently reused and juxtaposed with a donor duplication containing exons 8 and 9 from ancestral , creating four fusion genes that include lineage-specific members of the gene family. Combined analysis of >5,000 AMD cases and controls identifies a significant burden of a rare missense mutation that clusters at the N terminus of [ = 5.81 × 10, odds ratio (OR) = 9.8 (3.67-Infinity)]. A bipolar clustering pattern of rare nonsynonymous mutations in patients with AMD ( < 10) and AHUS ( = 0.0079) maps to functional domains that show evidence of positive selection during primate evolution. Our structural variation analysis in >2,400 individuals reveals five recurrent rearrangement breakpoints that show variable frequency among AMD cases and controls. These data suggest a dynamic and recurrent pattern of mutation critical to the emergence of new genes but also in the predisposition to complex human genetic disease phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1717600115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948961PMC
May 2018

A Deep Learning Algorithm for Prediction of Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration from Color Fundus Photography.

Ophthalmology 2018 09 10;125(9):1410-1420. Epub 2018 Apr 10.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany. Electronic address:

Purpose: Age-related macular degeneration (AMD) is a common threat to vision. While classification of disease stages is critical to understanding disease risk and progression, several systems based on color fundus photographs are known. Most of these require in-depth and time-consuming analysis of fundus images. Herein, we present an automated computer-based classification algorithm.

Design: Algorithm development for AMD classification based on a large collection of color fundus images. Validation is performed on a cross-sectional, population-based study.

Participants: We included 120 656 manually graded color fundus images from 3654 Age-Related Eye Disease Study (AREDS) participants. AREDS participants were >55 years of age, and non-AMD sight-threatening diseases were excluded at recruitment. In addition, performance of our algorithm was evaluated in 5555 fundus images from the population-based Kooperative Gesundheitsforschung in der Region Augsburg (KORA; Cooperative Health Research in the Region of Augsburg) study.

Methods: We defined 13 classes (9 AREDS steps, 3 late AMD stages, and 1 for ungradable images) and trained several convolution deep learning architectures. An ensemble of network architectures improved prediction accuracy. An independent dataset was used to evaluate the performance of our algorithm in a population-based study.

Main Outcome Measures: κ Statistics and accuracy to evaluate the concordance between predicted and expert human grader classification.

Results: A network ensemble of 6 different neural net architectures predicted the 13 classes in the AREDS test set with a quadratic weighted κ of 92% (95% confidence interval, 89%-92%) and an overall accuracy of 63.3%. In the independent KORA dataset, images wrongly classified as AMD were mainly the result of a macular reflex observed in young individuals. By restricting the KORA analysis to individuals >55 years of age and prior exclusion of other retinopathies, the weighted and unweighted κ increased to 50% and 63%, respectively. Importantly, the algorithm detected 84.2% of all fundus images with definite signs of early or late AMD. Overall, 94.3% of healthy fundus images were classified correctly.

Conclusions: Our deep learning algoritm revealed a weighted κ outperforming human graders in the AREDS study and is suitable to classify AMD fundus images in other datasets using individuals >55 years of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2018.02.037DOI Listing
September 2018

A mega-analysis of expression quantitative trait loci (eQTL) provides insight into the regulatory architecture of gene expression variation in liver.

Sci Rep 2018 04 12;8(1):5865. Epub 2018 Apr 12.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Genome-wide association studies (GWAS) have identified numerous genetic variants in the human genome associated with diseases and traits. Nevertheless, for most loci the causative variant is still unknown. Expression quantitative trait loci (eQTL) in disease relevant tissues is an excellent approach to correlate genetic association with gene expression. While liver is the primary site of gene transcription for two pathways relevant to age-related macular degeneration (AMD), namely the complement system and cholesterol metabolism, we explored the contribution of AMD associated variants to modulate liver gene expression. We extracted publicly available data and computed the largest eQTL data set for liver tissue to date. Genotypes and expression data from all studies underwent rigorous quality control. Subsequently, Matrix eQTL was used to identify significant local eQTL. In total, liver samples from 588 individuals revealed 202,489 significant eQTL variants affecting 1,959 genes (Q-Value < 0.001). In addition, a further 101 independent eQTL signals were identified in 93 of the 1,959 eQTL genes. Importantly, our results independently reinforce the notion that high density lipoprotein metabolism plays a role in AMD pathogenesis. Taken together, our study generated a first comprehensive map reflecting the genetic regulatory landscape of gene expression in liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-24219-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897392PMC
April 2018
-->