TY  - JOUR
A1  - Grassmann, Felix
A1  - Fritsche, Lars G.
A1  - Keilhauer, Claudia N.
A1  - Heid, Iris M.
A1  - Weber, Bernhard H. F.
T1  - Modelling the Genetic Risk in Age-Related Macular Degeneration
JF  - PLoS One
N2  - Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.
KW  - AMD
KW  - complement factor-H
KW  - grading system
KW  - United States
KW  - vitamin C
KW  - prevalence
KW  - variants
KW  - susceptibility
KW  - association
KW  - maculopathy
KW  - variant genotypes
KW  - genetic loci
KW  - macular degeneration
KW  - genetics of disease
KW  - eyes
KW  - cased-control studies
KW  - genotyping
KW  - human genetics
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131315
VL  - 7
IS  - 5
ER  - 
TY  - JOUR
A1  - Sbiera, Silviu
A1  - Ronchi, Cristina L.
A1  - Leich, Ellen
A1  - Henzel, Katharina
A1  - Rosenwald, Andreas
A1  - Allolio, Bruno
A1  - Fassnacht, Martin
T1  - Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence?
JF  - PLoS ONE
N2  - Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.
KW  - adenomas
KW  - cancer diagnosis
KW  - cancer detection
KW  - carcinogenesis
KW  - carcinomas
KW  - chromosomes
KW  - genetic loci
KW  - malignant tumors
KW  - notch signaling
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97218
ER  - 
TY  - JOUR
A1  - Hibar, Derrek P.
A1  - Adams, Hieab H.H.
A1  - Jahanshad, Neda
A1  - Chauhan, Ganesh
A1  - Stein, Jason L
A1  - Hofer, Edith
A1  - Renteria, Miguel E.
A1  - Bis, Joshua C.
A1  - Arias-Vasquez, Alejandro
A1  - Ikram, M. Kamran
A1  - Desrivières, Sylvane
A1  - Vernooij, Meike W.
A1  - Abramovic, Lucija
A1  - Alhusaini, Saud
A1  - Amin, Najaf
A1  - Andersson, Micael
A1  - Arfanakis, Konstantinos
A1  - Aribisala, Benjamin S.
A1  - Armstrong, Nicola J.
A1  - Athanasiu, Lavinia
A1  - Axelsson, Tomas
A1  - Beecham, Ashley H.
A1  - Beiser, Alexa
A1  - Bernard, Manon
A1  - Blanton, Susan H.
A1  - Bohlken, Marc M.
A1  - Boks, Marco P.
A1  - Bralten, Janita
A1  - Brickman, Adam M.
A1  - Carmichael, Owen
T1  - Novel genetic loci associated with hippocampal volume
JF  - Nature Communications
N2  - The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (r\(_g\)=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
KW  - brain
KW  - hippocampal formation
KW  - neuropsychiatric disorders
KW  - Alzheimer’s disease
KW  - genetic loci
KW  - hippocampal volume
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-182115
VL  - 8
ER  - 
TY  - JOUR
A1  - Klughammer, Johanna
A1  - Dittrich, Marcus
A1  - Blom, Jochen
A1  - Mitesser, Vera
A1  - Vogel, Ulrich
A1  - Frosch, Matthias
A1  - Goesmann, Alexander
A1  - Müller, Tobias
A1  - Schoen, Christoph
T1  - Comparative genome sequencing reveals within-host genetic changes in Neisseria meningitidis during invasive disease
JF  - PLoS ONE
N2  - Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo.
KW  - blood
KW  - comparative genomics
KW  - throat
KW  - genetic loci
KW  - Neisseria meningitidis
KW  - genomic libraries
KW  - genome sequencing
KW  - sequence assembly tools
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159547
VL  - 12
IS  - 1
ER  -