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Published year: 20204
Author: Katrin Horn4
Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease
Genetical Statistics and Systems Biology

Abstract (Expand)

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- 8), (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.

Authors: Thomas W. Winkler, Felix Grassmann, Caroline Brandl, Christina Kiel, Felix Günther, Tobias Strunz, Lorraine Weidner, Martina E. Zimmermann, Christina A. Korb, Alicia Poplawski, Alexander K. Schuster, Martina Müller-Nurasyid, Annette Peters, Franziska G. Rauscher, Tobias Elze, Katrin Horn, Markus Scholz, Marisa Cañadas-Garre, Amy Jayne McKnight, Nicola Quinn, Ruth E. Hogg, Helmut Küchenhoff, Iris M. Heid, Klaus J. Stark, Bernhard H. F. Weber

Date Published: 1st Dec 2020

Publication Type: Journal article

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for … rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Authors: M. Gorski, B. Jung, Y. Li, P. R. Matias-Garcia, M. Wuttke, S. Coassin, C. H. L. Thio, M. E. Kleber, T. W. Winkler, V. Wanner, J. F. Chai, A. Y. Chu, M. Cocca, M. F. Feitosa, S. Ghasemi, A. Hoppmann, K. Horn, M. Li, T. Nutile, M. Scholz, K. B. Sieber, A. Teumer, A. Tin, J. Wang, B. O. Tayo, T. S. Ahluwalia, P. Almgren, S. J. L. Bakker, B. Banas, N. Bansal, M. L. Biggs, E. Boerwinkle, E. P. Bottinger, H. Brenner, R. J. Carroll, J. Chalmers, M. L. Chee, M. L. Chee, C. Y. Cheng, J. Coresh, M. H. de Borst, F. Degenhardt, K. U. Eckardt, K. Endlich, A. Franke, S. Freitag-Wolf, P. Gampawar, R. T. Gansevoort, M. Ghanbari, C. Gieger, P. Hamet, K. Ho, E. Hofer, B. Holleczek, V. H. Xian Foo, N. Hutri-Kahonen, S. J. Hwang, M. A. Ikram, N. S. Josyula, M. Kahonen, C. C. Khor, W. Koenig, H. Kramer, B. K. Kramer, B. Kuhnel, L. A. Lange, T. Lehtimaki, W. Lieb, R. J. F. Loos, M. A. Lukas, L. P. Lyytikainen, C. Meisinger, T. Meitinger, O. Melander, Y. Milaneschi, P. P. Mishra, N. Mononen, J. C. Mychaleckyj, G. N. Nadkarni, M. Nauck, K. Nikus, B. Ning, I. M. Nolte, M. L. O'Donoghue, M. Orho-Melander, S. A. Pendergrass, B. W. J. H. Penninx, M. H. Preuss, B. M. Psaty, L. M. Raffield, O. T. Raitakari, R. Rettig, M. Rheinberger, K. M. Rice, A. R. Rosenkranz, P. Rossing, J. I. Rotter, C. Sabanayagam, H. Schmidt, R. Schmidt, B. Schottker, C. A. Schulz, S. Sedaghat, C. M. Shaffer, K. Strauch, S. Szymczak, K. D. Taylor, J. Tremblay, L. Chaker, P. van der Harst, P. J. van der Most, N. Verweij, U. Volker, M. Waldenberger, L. Wallentin, D. M. Waterworth, H. D. White, J. G. Wilson, T. Y. Wong, M. Woodward, Q. Yang, M. Yasuda, L. M. Yerges-Armstrong, Y. Zhang, H. Snieder, C. Wanner, C. A. Boger, A. Kottgen, F. Kronenberg, C. Pattaro, I. M. Heid

Date Published: 30th Oct 2020

Publication Type: Journal article

Genome-wide analysis of carotid plaque burden suggests a role of IL5 in men.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Carotid artery plaque is an established marker of subclinical atherosclerosis with pronounced sex-dimorphism. Here, we aimed to identify genetic variants associated with carotid plaque … burden (CPB) and to examine potential sex-specific genetic effects on plaque sizes. METHODS AND RESULTS: We defined six operationalizations of CPB considering plaques in common carotid arteries, carotid bulb, and internal carotid arteries. We performed sex-specific genome-wide association analyses for all traits in the LIFE-Adult cohort (n = 727 men and n = 550 women) and tested significantly associated loci for sex-specific effects. In order to identify causal genes, we analyzed candidate gene expression data for correlation with CPB traits and corresponding sex-specific effects. Further, we tested if previously reported SNP associations with CAD and plaque prevalence are also associated with CBP. We found seven loci with suggestive significance for CPB (p<3.33x10-7), explaining together between 6 and 13% of the CPB variance. Sex-specific analysis showed a genome-wide significant hit for men at 5q31.1 (rs201629990, beta = -0.401, p = 5.22x10-9), which was not associated in women (beta = -0.127, p = 0.093) with a significant difference in effect size (p = 0.008). Analyses of gene expression data suggested IL5 as the most plausible candidate, as it reflected the same sex-specific association with CPBs (p = 0.037). Known plaque prevalence or CAD loci showed no enrichment in the association with CPB. CONCLUSIONS: We showed that CPB is a complementary trait in analyzing genetics of subclinical atherosclerosis. We detected a novel locus for plaque size in men only suggesting a role of IL5. Several estrogen response elements in this locus point towards a functional explanation of the observed sex-specific effect.

Authors: J. Pott, F. Beutner, K. Horn, H. Kirsten, K. Olischer, K. Wirkner, M. Loeffler, M. Scholz

Date Published: 30th May 2020

Publication Type: Journal article

Human Diseases: cardiovascular system disease, atherosclerosis

HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non-Insulin-Treated Type 2 Diabetes
Genetical Statistics and Systems Biology

Abstract (Expand)

CONTEXT Common genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type …e 1 diabetes, the aim of the present study was to test the association of high density imputed human leukocyte antigen (HLA) genotypes with type 2 diabetes. OBJECTIVES AND DESIGN Three cohorts (Ntotal = 10 413) from Leipzig, Germany were included in this study: LIFE-Adult (N = 4649), LIFE-Heart (N = 4815) and the Sorbs (N = 949) cohort. Detailed metabolic phenotyping and genome-wide single nucleotide polymorphism (SNP) data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4-digit level and association tests for type 2 diabetes, and related metabolic traits were conducted. RESULTS In a meta-analysis including all 3 cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (P = 0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (P = 0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02, which was also associated with reduced risk of type 2 diabetes (OR 0.84; P = 0.005). On the contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non-insulin-treated diabetes (OR 1.37; P = 0.002). CONCLUSIONS Genetic variation in the HLA class II locus exerts risk and protective effects on non-insulin-treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.

Authors: Thomas Jacobi, Lucas Massier, Nora Klöting, Katrin Horn, Alexander Schuch, Peter Ahnert, Christoph Engel, Markus Löffler, Ralph Burkhardt, Joachim Thiery, Anke Tönjes, Michael Stumvoll, Matthias Blüher, Ilias Doxiadis, Markus Scholz, Peter Kovacs

Date Published: 1st Mar 2020

Publication Type: Journal article

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