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1. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Author

Franceschini N, Giambartolomei C, de Vries PS, Finan C, Bis JC, Huntley RP, Lovering RC, Tajuddin SM, Winkler TW, Graff M, Kavousi M, Dale C, Smith AV, Hofer E, van Leeuwen EM, Nolte IM, Lu L, Scholz M, Sargurupremraj M, Pitkänen N, Franzén O, Joshi PK, Noordam R, Marioni RE, Hwang SJ, Musani SK, Schminke U, Palmas W, Isaacs A, Correa A, Zonderman AB, Hofman A, Teumer A, Cox AJ, Uitterlinden AG, Wong A, Smit AJ, Newman AB, Britton A, Ruusalepp A, Sennblad B, Hedblad B, Pasaniuc B, Penninx BW, Langefeld CD, Wassel CL, Tzourio C, Fava C, Baldassarre D, O'Leary DH, Teupser D, Kuh D, Tremoli E, Mannarino E, Grossi E, Boerwinkle E, Schadt EE, Ingelsson E, Veglia F, Rivadeneira F, Beutner F, Chauhan G, Heiss G, Snieder H, Campbell H, Völzke H, Markus HS, Deary IJ, Jukema JW, de Graaf J, Price J, Pott J, Hopewell JC, Liang J, Thiery J, Engmann J, Gertow K, Rice K, Taylor KD, Dhana K, Kiemeney LALM, Lind L, Raffield LM, Launer LJ, Holdt LM, Dörr M, Dichgans M, Traylor M, Sitzer M, Kumari M, Kivimaki M, Nalls MA, Melander O, Raitakari O, Franco OH, Rueda-Ochoa OL, Roussos P, Whincup PH, Amouyel P, Giral P, Anugu P, Wong Q, Malik R, Rauramaa R, Burkhardt R, Hardy R, Schmidt R, de Mutsert R, Morris RW, Strawbridge RJ, Wannamethee SG, Hägg S, Shah S, McLachlan S, Trompet S, Seshadri S, Kurl S, Heckbert SR, Ring S, Harris TB, Lehtimäki T, Galesloot TE, Shah T, de Faire U, Plagnol V, Rosamond WD, Post W, Zhu X, Zhang X, Guo X, Saba Y, Dehghan A, Seldenrijk A, Morrison AC, Hamsten A, Psaty BM, van Duijn CM, Lawlor DA, Mook-Kanamori DO, Bowden DW, Schmidt H, Wilson JF, Wilson JG, Rotter JI, Wardlaw JM, Deanfield J, Halcox J, Lyytikäinen LP, Loeffler M, Evans MK, Debette S, Humphries SE, Völker U, Gudnason V, Hingorani AD, Björkegren JLM, Casas JP, and O'Donnell CJ

Subjects
ADAMTS9 Protein genetics, Amino Acid Oxidoreductases genetics, Coronary Disease pathology, Humans, Lod Score, Plaque, Atherosclerotic pathology, Polymorphism, Single Nucleotide, Protein-Lysine 6-Oxidase, Quantitative Trait Loci genetics, Risk Factors, Carotid Intima-Media Thickness, Coronary Disease genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Plaque, Atherosclerotic genetics
Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018
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2. Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.

Author

Tönjes A, Scholz M, Krüger J, Krause K, Schleinitz D, Kirsten H, Gebhardt C, Marzi C, Grallert H, Ladenvall C, Heyne H, Laurila E, Kriebel J, Meisinger C, Rathmann W, Gieger C, Groop L, Prokopenko I, Isomaa B, Beutner F, Kratzsch J, Fischer-Rosinsky A, Pfeiffer A, Krohn K, Spranger J, Thiery J, Blüher M, Stumvoll M, and Kovacs P

Subjects
Animals, Genotype, Humans, Leukocytes, Mononuclear metabolism, Mice, Phosphoproteins genetics, Phosphoproteins metabolism, Polymorphism, Single Nucleotide genetics, RNA, Messenger metabolism, Genome-Wide Association Study methods, Progranulins blood
Abstract

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 × 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 × 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion., (© The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2018
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3. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.

Author

Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, Saleheen D, Kyriakou T, Nelson CP, Hopewell JC, Webb TR, Zeng L, Dehghan A, Alver M, Armasu SM, Auro K, Bjonnes A, Chasman DI, Chen S, Ford I, Franceschini N, Gieger C, Grace C, Gustafsson S, Huang J, Hwang SJ, Kim YK, Kleber ME, Lau KW, Lu X, Lu Y, Lyytikäinen LP, Mihailov E, Morrison AC, Pervjakova N, Qu L, Rose LM, Salfati E, Saxena R, Scholz M, Smith AV, Tikkanen E, Uitterlinden A, Yang X, Zhang W, Zhao W, de Andrade M, de Vries PS, van Zuydam NR, Anand SS, Bertram L, Beutner F, Dedoussis G, Frossard P, Gauguier D, Goodall AH, Gottesman O, Haber M, Han BG, Huang J, Jalilzadeh S, Kessler T, König IR, Lannfelt L, Lieb W, Lind L, Lindgren CM, Lokki ML, Magnusson PK, Mallick NH, Mehra N, Meitinger T, Memon FU, Morris AP, Nieminen MS, Pedersen NL, Peters A, Rallidis LS, Rasheed A, Samuel M, Shah SH, Sinisalo J, Stirrups KE, Trompet S, Wang L, Zaman KS, Ardissino D, Boerwinkle E, Borecki IB, Bottinger EP, Buring JE, Chambers JC, Collins R, Cupples LA, Danesh J, Demuth I, Elosua R, Epstein SE, Esko T, Feitosa MF, Franco OH, Franzosi MG, Granger CB, Gu D, Gudnason V, Hall AS, Hamsten A, Harris TB, Hazen SL, Hengstenberg C, Hofman A, Ingelsson E, Iribarren C, Jukema JW, Karhunen PJ, Kim BJ, Kooner JS, Kullo IJ, Lehtimäki T, Loos RJF, Melander O, Metspalu A, März W, Palmer CN, Perola M, Quertermous T, Rader DJ, Ridker PM, Ripatti S, Roberts R, Salomaa V, Sanghera DK, Schwartz SM, Seedorf U, Stewart AF, Stott DJ, Thiery J, Zalloua PA, O'Donnell CJ, Reilly MP, Assimes TL, Thompson JR, Erdmann J, Clarke R, Watkins H, Kathiresan S, McPherson R, Deloukas P, Schunkert H, Samani NJ, and Farrall M

Subjects
Humans, Phenotype, Coronary Artery Disease genetics, Genome, Human, Genome-Wide Association Study
Abstract

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Published
2015
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4. Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

Author

Burkhardt R, Kirsten H, Beutner F, Holdt LM, Gross A, Teren A, Tönjes A, Becker S, Krohn K, Kovacs P, Stumvoll M, Teupser D, Thiery J, Ceglarek U, and Scholz M

Subjects
Carnitine blood, Cohort Studies, Disease genetics, Humans, Quantitative Trait Loci, Amino Acids blood, Carnitine analogs & derivatives, Gene Expression Profiling, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.

Published
2015
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5. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Franceschini, N, Giambartolomei, C, de Vries, PS, Finan, C, Bis, JC, Huntley, RP, Lovering, RC, Tajuddin, SM, Winkler, TW, Graff, M, Kavousi, M, Dale, C, Smith, AV, Hofer, E, van Leeuwen, EM, Nolte, IM, Lu, L, Scholz, M, Sargurupremraj, M, Pitkänen, N, Franzén, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, SJ, Musani, SK, Schminke, U, Palmas, W, Isaacs, A, Correa, A, Zonderman, AB, Hofman, A, Teumer, A, Cox, AJ, Uitterlinden, AG, Wong, A, Smit, AJ, Newman, AB, Britton, A, Ruusalepp, A, Sennblad, B, Hedblad, B, Pasaniuc, B, Penninx, BW, Langefeld, CD, Wassel, CL, Tzourio, C, Fava, C, Baldassarre, D, O’Leary, DH, Teupser, D, Kuh, D, Tremoli, E, Mannarino, E, Grossi, E, Boerwinkle, E, Schadt, EE, Ingelsson, E, Veglia, F, Rivadeneira, F, Beutner, F, Chauhan, G, Heiss, G, Snieder, H, Campbell, H, Völzke, H, Markus, HS, Deary, IJ, Jukema, JW, de Graaf, J, Price, J, Pott, J, Hopewell, JC, Liang, J, Thiery, J, Engmann, J, Gertow, K, Rice, K, Taylor, KD, Dhana, K, Kiemeney, LALM, Lind, L, Raffield, LM, Launer, LJ, Holdt, LM, Dörr, M, Dichgans, M, Traylor, M, Sitzer, M, Kumari, M, Kivimaki, M, Nalls, MA, Melander, O, Raitakari, O, Franco, OH, Rueda-Ochoa, OL, Roussos, P, Whincup, PH, Amouyel, P, and Giral, P

Subjects
Aging, MEGASTROKE Consortium, Quantitative Trait Loci, ADAMTS9 Protein, Coronary Disease, Cardiovascular, Polymorphism, Single Nucleotide, Carotid Intima-Media Thickness, Protein-Lysine 6-Oxidase, Risk Factors, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Aetiology, Polymorphism, Heart Disease - Coronary Heart Disease, Plaque, Atherosclerotic, Human Genome, Single Nucleotide, Atherosclerosis, Plaque, Atherosclerotic, Brain Disorders, Stroke, Heart Disease, cardiovascular system, Amino Acid Oxidoreductases, Lod Score, Genome-Wide Association Study
Abstract

© 2018, The Author(s). Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018

6. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Author

Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K.E., Zheng, Z., Yengo, L., Lloyd-Jones, L.R., Sidorenko, J., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.-J., Franke, L., Frayling, T., Gharib, S., Gibson, G., Hemani, G., Jansen, R., Kähönen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Metspalu, A., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Meurs, J., Verlouw, J., Völker, U., Võsa, U., Yaghootkar, H., Zeng, B., McRae, A.F., Visscher, P.M., Zeng, J., Yang, J., Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Clinicum, Complex Disease Genetics, Psychiatry, APH - Digital Health, and Internal Medicine

Subjects
0301 basic medicine, Epigenomics, Netherlands Twin Register (NTR), endocrine system diseases, General Physics and Astronomy, Genome-wide association study, Epigenesis, Genetic, Genotype, lcsh:Science, Heat-Shock Proteins, Genetics, Multidisciplinary, Mitochondrial Proton-Translocating ATPases, 3. Good health, DNA methylation, Risk, endocrine system, Science, education, Biology, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Humans, Genetic Predisposition to Disease, Epigenetics, Gene, Genetic association, Genetic Variation, nutritional and metabolic diseases, General Chemistry, DNA Methylation, 030104 developmental biology, Calcium-Calmodulin-Dependent Protein Kinase Type 1, Diabetes Mellitus, Type 2, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, lcsh:Q, 3111 Biomedicine, Carrier Proteins, human activities, Genome-Wide Association Study
Abstract

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants., GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.

Published
2018

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