Filter and export

Publications

227 Publications visible to you, out of a total of 227
Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND PURPOSE Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, …, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Authors: Nicola J. Armstrong, Karen A. Mather, Muralidharan Sargurupremraj, Maria J. Knol, Rainer Malik, Claudia L. Satizabal, Lisa R. Yanek, Wei Wen, Vilmundur G. Gudnason, Nicole D. Dueker, Lloyd T. Elliott, Edith Hofer, Joshua Bis, Neda Jahanshad, Shuo Li, Mark A. Logue, Michelle Luciano, Markus Scholz, Albert V. Smith, Stella Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S. Beiser, Henry Brodaty, Ian J. Deary, Christine Fennema-Notestine, Piyush G. Gampawar, Rebecca Gottesman, Ludovica Griffanti, Clifford R. Jack, Mark Jenkinson, Jiyang Jiang, Brian G. Kral, John B. Kwok, Leonie Lampe, David C M Liewald, Pauline Maillard, Jonathan Marchini, Mark E. Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V. Roshchupkin, Peter R. Schofield, Matthias L. Schroeter, David J. Stott, Anbupalam Thalamuthu, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W. Vernooij, Veronica A. Witte, Margaret J. Wright, Qiong Yang, Zoe Morris, Siggi Siggurdsson, Bruce Psaty, Arno Villringer, Helena Schmidt, Asta K. Haberg, Cornelia M. van Duijn, J. Wouter Jukema, Martin Dichgans, Ralph L. Sacco, Clinton B. Wright, William S. Kremen, Lewis C. Becker, Paul M. Thompson, Thomas H. Mosley, Joanna M. Wardlaw, M. Arfan Ikram, Hieab H. H. Adams, Sudha Seshadri, Perminder S. Sachdev, Stephen M. Smith, Lenore Launer, William Longstreth, Charles DeCarli, Reinhold Schmidt, Myriam Fornage, Stephanie Debette, Paul A. Nyquist

Date Published: 1st Jul 2020

Publication Type: Journal article

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.
Genetical Statistics and Systems Biology

Abstract (Expand)

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their … surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one’s occupation.

Authors: Jean Shin, Shaojie Ma, Edith Hofer, Yash Patel, Daniel E. Vosberg, Steven Tilley, Gennady V. Roshchupkin, André M. M. Sousa, Xueqiu Jian, Rebecca Gottesman, Thomas H. Mosley, Myriam Fornage, Yasaman Saba, Lukas Pirpamer, Reinhold Schmidt, Helena Schmidt, Amaia Carrion-Castillo, Fabrice Crivello, Bernard Mazoyer, Joshua C. Bis, Shuo Li, Qiong Yang, Michelle Luciano, Sherif Karama, Lindsay Lewis, Mark E. Bastin, Mathew A. Harris, Joanna M. Wardlaw, Ian E. Deary, Markus Scholz, Markus Loeffler, A. Veronica Witte, Frauke Beyer, Arno Villringer, Nicola J. Armstrong, Karen A. Mather, David Ames, Jiyang Jiang, John B. Kwok, Peter R. Schofield, Anbupalam Thalamuthu, Julian N. Trollor, Margaret J. Wright, Henry Brodaty, Wei Wen, Perminder S. Sachdev, Natalie Terzikhan, Tavia E. Evans, Hieab H. H. H. Adams, M. Arfan Ikram, Stefan Frenzel, Sandra van der Auwera-Palitschka, Katharina Wittfeld, Robin Bülow, Hans Jörgen Grabe, Christophe Tzourio, Aniket Mishra, Sophie Maingault, Stephanie Debette, Nathan A. Gillespie, Carol E. Franz, William S. Kremen, Linda Ding, Neda Jahanshad, Nenad Sestan, Zdenka Pausova, Sudha Seshadri, Tomas Paus

Date Published: 1st Jun 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

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.
Genetical Statistics and Systems Biology

Abstract (Expand)

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we … evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (\textgreekb = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (\textgreekb = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (\textgreekb = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p \textgreater 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

Authors: Yan Zheng, Tao Huang, Tiange Wang, Zhendong Mei, Zhonghan Sun, Tao Zhang, Christina Ellervik, Jin-Fang Chai, Xueling Sim, Rob M. van Dam, E-Shyong Tai, Woon-Puay Koh, Rajkumar Dorajoo, Seang-Mei Saw, Charumathi Sabanayagam, Tien Yin Wong, Preeti Gupta, Peter Rossing, Tarunveer S. Ahluwalia, Rebecca K. Vinding, Hans Bisgaard, Klaus Bønnelykke, Yujie Wang, Mariaelisa Graff, Trudy Voortman, Frank J. A. van Rooij, Albert Hofman, Diana van Heemst, Raymond Noordam, Angela C. Estampador, Tibor V. Varga, Cornelia Enzenbach, Markus Scholz, Joachim Thiery, Ralph Burkhardt, Marju Orho-Melander, Christina-Alexandra Schulz, Ulrika Ericson, Emily Sonestedt, Michiaki Kubo, Masato Akiyama, Ang Zhou, Tuomas O. Kilpeläinen, Torben Hansen, Marcus E. Kleber, Graciela Delgado, Mark McCarthy, Rozenn N. Lemaitre, Janine F. Felix, Vincent W. V. Jaddoe, Ying Wu, Karen L. Mohlke, Terho Lehtimäki, Carol A. Wang, Craig E. Pennell, Heribert Schunkert, Thorsten Kessler, Lingyao Zeng, Christina Willenborg, Annette Peters, Wolfgang Lieb, Veit Grote, Peter Rzehak, Berthold Koletzko, Jeanette Erdmann, Matthias Munz, Tangchun Wu, Meian He, Caizheng Yu, Cécile Lecoeur, Philippe Froguel, Dolores Corella, Luis A. Moreno, Chao-Qiang Lai, Niina Pitkänen, Colin A. Boreham, Paul M. Ridker, Frits R. Rosendaal, Renée de Mutsert, Chris Power, Lavinia Paternoster, Thorkild I. A. Sørensen, Anne Tjønneland, Kim Overvad, Luc Djousse, Fernando Rivadeneira, Nanette R. Lee, Olli T. Raitakari, Mika Kähönen, Jorma Viikari, Jean-Paul Langhendries, Joaquin Escribano, Elvira Verduci, George Dedoussis, Inke König, Beverley Balkau, Oscar Coltell, Jean Dallongeville, Aline Meirhaeghe, Philippe Amouyel, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Winfried März, David A. Mackey, Dariusz Gruszfeld, Katherine L. Tucker, Frédéric Fumeron, Ramon Estruch, Jose M. Ordovas, Donna K. Arnett, Dennis O. Mook-Kanamori, Dariush Mozaffarian, Bruce M. Psaty, Kari E. North, Daniel I. Chasman, Lu Qi

Date Published: 7th May 2020

Publication Type: Journal article

The emergence of dyslexia in the developing brain
Genetical Statistics and Systems Biology

Abstract (Expand)

Developmental dyslexia, a severe deficit in literacy learning, is a neurodevelopmental learning disorder. Yet, it is not clear whether existing neurobiological accounts of dyslexia capture potential … predispositions of the deficit or consequences of reduced reading experience. Here, we longitudinally followed 32 children from preliterate to school age using functional and structural magnetic resonance imaging techniques. Based on standardised and age-normed reading and spelling tests administered at school age, children were classified as 16 dyslexic participants and 16 controls. This longitudinal design allowed us to disentangle possible neurobiological predispositions for developing dyslexia from effects of individual differences in literacy experience. In our sample, the disorder can be predicted already before literacy learning from auditory cortex gyrification and aberrant downstream connectivity within the speech processing system. These results provide evidence for the notion that dyslexia may originate from an atypical maturation of the speech network that precedes literacy instruction.

Authors: Ulrike Kuhl, Nicole E. Neef, Indra Kraft, Gesa Schaadt, Liane Dörr, Jens Brauer, Ivonne Czepezauer, Bent Müller, Arndt Wilcke, Holger Kirsten, Frank Emmrich, Johannes Boltze, Angela D. Friederici, Michael A. Skeide

Date Published: 1st May 2020

Publication Type: Journal article

Adipocytokines are not associated with gestational diabetes mellitus but with pregnancy status.
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS Adipose tissue-secreted proteins, i.e. adipocytokines, have been identified as potential mediators linking fat mass and adipose tissue dysfunction with impaired glucose homeostasis, alterations …s in the inflammatory status, and risk of diabetes. The aim of this study was to determine whether seven circulating adipocytokines are associated with gestational diabetes mellitus (GDM) or are altered by metabolic and weight changes during pregnancy itself. METHODS A panel of seven adipocytokines (i.e. adiponectin, adipocyte fatty acid-binding protein, chemerin, leptin, Pro-Enkephalin, progranulin, and Pro-Neurotensin) was quantified in serum in a cross-sectional cohort of 222 women with the following three groups matched for age and body mass index: (i) 74 pregnant women with GDM; (ii) 74 pregnant women without GDM; and (iii) 74 non-pregnant and healthy women. A stepwise statistical approach was used by performing pairwise comparisons, principal component analysis (PCA), and partial least square discriminant analysis (PLS-DA). RESULTS Five out of seven adipocytokines were dysregulated between pregnant and non-pregnant women, i.e. adiponectin, chemerin, leptin, Pro-Enkephalin, and progranulin. None of the adipocytokines significantly differed between GDM and non-GDM status during pregnancy. The same five adipocytokines clustered in a principal component representing pregnancy-induced effects. Fasting insulin was the most relevant parameter in the discrimination of GDM as compared to pregnant women without GDM, whereas chemerin and adiponectin were most relevant factors to discriminate pregnancy status. CONCLUSIONS Pregnancy status but not presence of GDM can be distinguished by the seven investigated adipocytokines in discrimination analyses.

Authors: Thomas Ebert, Claudia Gebhardt, Markus Scholz, Dorit Schleinitz, Matthias Blüher, Michael Stumvoll, Peter Kovacs, Mathias Fasshauer, Anke Tönjes

Date Published: 10th Apr 2020

Publication Type: Journal article

Relation of Whole Blood Amino Acid and Acylcarnitine Metabolome to Age, Sex, BMI, Puberty, and Metabolic Markers in Children and Adolescents
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Changes in the metabolic fingerprint of blood during child growth and development are a largely under-investigated area of research. The examination of such aspects requires a cohort of …f healthy children and adolescents who have been subjected to deep phenotyping, including collection of biospecimens for metabolomic analysis. The present study considered whether amino acid (AA) and acylcarnitine (AC) concentrations are associated with age, sex, body mass index (BMI), and puberty during childhood and adolescence. It also investigated whether there are associations between amino acids (AAs) and acylcarnitines (ACs) and laboratory parameters of glucose and lipid metabolism, as well as liver, kidney, and thyroid parameters. METHODS A total of 3989 dried whole blood samples collected from 2191 healthy participants, aged 3 months to 18 years, from the LIFE Child cohort (Leipzig, Germany) were analyzed using liquid chromatography tandem mass spectrometry to detect levels of 23 AAs, 6 ACs, and free carnitine (C0). Age- and sex-related percentiles were estimated for each metabolite. In addition, correlations between laboratory parameters and levels of the selected AAs and ACs were calculated using hierarchical models. RESULTS Four different age-dependent profile types were identified for AAs and ACs. Investigating the association with puberty, we mainly identified peak metabolite levels at Tanner stages 2 to 3 in girls and stages 3 to 5 in boys. Significant correlations were observed between BMI standard deviation score (BMI-SDS) and certain metabolites, among them, branched-chain (leucine/isoleucine, valine) and aromatic (phenylalanine, tyrosine) amino acids. Most of the metabolites correlated significantly with absolute concentrations of glucose, glycated hemoglobin (HbA1c), triglycerides, cystatin C (CysC), and creatinine. After age adjustment, significant correlations were observed between most metabolites and CysC, as well as HbA1c. CONCLUSIONS During childhood, several AA and AC levels are related to age, sex, BMI, and puberty. Moreover, our data verified known associations but also revealed new correlations between AAs/ACs and specific key markers of metabolic function.

Authors: Josephin Hirschel, Mandy Vogel, Ronny Baber, Antje Garten, Carl Beuchel, Yvonne Dietz, Julia Dittrich, Antje Körner, Wieland Kiess, Uta Ceglarek

Date Published: 1st Apr 2020

Publication Type: Journal article

Navigate

Health Atlas - Local Data Hub/Leipzig

The Health Atlas - Local Data Hub/Leipzig is an alliance of medical ontologists, medical systems biologists and clinical trials groups to design and implement a multi-functional and quality-assured atlas. It provides models, data and metadata on specific use cases from medical research fields.

Registered Repository

re3data.org Badge
Powered by
 (v.1.13.0-master)
Health Atlas | Funding and Programmes | Credits | Terms & Conditions | Privacy Policy | Imprint
Copyright © 2008 - 2021 The University of Manchester and HITS gGmbH
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig

By continuing to use this site you agree to the use of cookies