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1. Targeting immune–fibroblast cell communication in heart failure

Author

Amrute, Junedh M., Luo, Xin, Penna, Vinay, Yang, Steven, Yamawaki, Tracy, Hayat, Sikander, Bredemeyer, Andrea, Jung, In-Hyuk, Kadyrov, Farid F., Heo, Gyu Seong, Venkatesan, Rajiu, Shi, Sally Yu, Parvathaneni, Alekhya, Koenig, Andrew L., Kuppe, Christoph, Baker, Candice, Luehmann, Hannah, Jones, Cameran, Kopecky, Benjamin, Zeng, Xue, Bleckwehl, Tore, Ma, Pan, Lee, Paul, Terada, Yuriko, Fu, Angela, Furtado, Milena, Kreisel, Daniel, Kovacs, Atilla, Stitziel, Nathan O., Jackson, Simon, Li, Chi-Ming, Liu, Yongjian, Rosenthal, Nadia A., Kramann, Rafael, Ason, Brandon, and Lavine, Kory J.

Published
2024
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2. Rare variant contribution to the heritability of coronary artery disease

Author

Rocheleau, Ghislain, Clarke, Shoa L., Auguste, Gaëlle, Hasbani, Natalie R., Morrison, Alanna C., Heath, Adam S., Bielak, Lawrence F., Iyer, Kruthika R., Young, Erica P., Stitziel, Nathan O., Jun, Goo, Laurie, Cecelia, Broome, Jai G., Khan, Alyna T., Arnett, Donna K., Becker, Lewis C., Bis, Joshua C., Boerwinkle, Eric, Bowden, Donald W., Carson, April P., Ellinor, Patrick T., Fornage, Myriam, Franceschini, Nora, Freedman, Barry I., Heard-Costa, Nancy L., Hou, Lifang, Chen, Yii-Der Ida, Kenny, Eimear E., Kooperberg, Charles, Kral, Brian G., Loos, Ruth J. F., Lutz, Sharon M., Manson, JoAnn E., Martin, Lisa W., Mitchell, Braxton D., Nassir, Rami, Palmer, Nicholette D., Post, Wendy S., Preuss, Michael H., Psaty, Bruce M., Raffield, Laura M., Regan, Elizabeth A., Rich, Stephen S., Smith, Jennifer A., Taylor, Kent D., Yanek, Lisa R., Young, Kendra A., Hilliard, Austin T., Tcheandjieu, Catherine, Peyser, Patricia A., Vasan, Ramachandran S., Rotter, Jerome I., Miller, Clint L., Assimes, Themistocles L., de Vries, Paul S., and Do, Ron

Published
2024
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4. Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk

Author

Zhang, Xiangyu, Kapoor, Divya, Jeong, Se-Jin, Fappi, Alan, Stitham, Jeremiah, Shabrish, Vasavi, Sergin, Ismail, Yousif, Eman, Rodriguez-Velez, Astrid, Yeh, Yu-Sheng, Park, Arick, Yurdagul, Jr, Arif, Rom, Oren, Epelman, Slava, Schilling, Joel D., Sardiello, Marco, Diwan, Abhinav, Cho, Jaehyung, Stitziel, Nathan O., Javaheri, Ali, Lodhi, Irfan J., Mittendorfer, Bettina, and Razani, Babak

Published
2024
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5. Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification

Author

de Vries, Paul S., Conomos, Matthew P., Singh, Kuldeep, Nicholson, Christopher J., Jain, Deepti, Hasbani, Natalie R., Jiang, Wanlin, Lee, Sujin, Lino Cardenas, Christian L., Lutz, Sharon M., Wong, Doris, Guo, Xiuqing, Yao, Jie, Young, Erica P., Tcheandjieu, Catherine, Hilliard, Austin T., Bis, Joshua C., Bielak, Lawrence F., Brown, Michael R., Musharoff, Shaila, Clarke, Shoa L., Terry, James G., Palmer, Nicholette D., Yanek, Lisa R., Xu, Huichun, Heard-Costa, Nancy, Wessel, Jennifer, Selvaraj, Margaret Sunitha, Li, Rebecca H., Sun, Xiao, Turner, Adam W., Stilp, Adrienne M., Khan, Alyna, Newman, Anne B., Rasheed, Asif, Freedman, Barry I., Kral, Brian G., McHugh, Caitlin P., Hodonsky, Chani, Saleheen, Danish, Herrington, David M., Jacobs, Jr, David R., Nickerson, Deborah A., Boerwinkle, Eric, Wang, Fei Fei, Heiss, Gerardo, Jun, Goo, Kinney, Greg L., Sigurslid, Haakon H., Doddapaneni, HarshaVardhan, Hall, Ira M., Bensenor, Isabela M., Broome, Jai, Crapo, James D., Wilson, James G., Smith, Jennifer A., Blangero, John, Vargas, Jose D., Mosquera, Jose Verdezoto, Smith, Joshua D., Viaud-Martinez, Karine A., Ryan, Kathleen A., Young, Kendra A., Taylor, Kent D., Lange, Leslie A., Emery, Leslie S., Bittencourt, Marcio S., Budoff, Matthew J., Montasser, May E., Yu, Miao, Mahaney, Michael C., Mahamdeh, Mohammed S., Fornage, Myriam, Franceschini, Nora, Lotufo, Paulo A., Natarajan, Pradeep, Wong, Quenna, Mathias, Rasika A., Gibbs, Richard A., Do, Ron, Mehran, Roxana, Tracy, Russell P., Kim, Ryan W., Nelson, Sarah C., Damrauer, Scott M., Kardia, Sharon L. R., Rich, Stephen S., Fuster, Valentin, Napolioni, Valerio, Zhao, Wei, Tian, Wenjie, Yin, Xianyong, Min, Yuan-I, Manning, Alisa K., Peloso, Gina, Kelly, Tanika N., O’Donnell, Christopher J., Morrison, Alanna C., Curran, Joanne E., Zapol, Warren M., Bowden, Donald W., Becker, Lewis C., Correa, Adolfo, Mitchell, Braxton D., Psaty, Bruce M., Carr, John Jeffrey, Pereira, Alexandre C., Assimes, Themistocles L., Stitziel, Nathan O., Hokanson, John E., Laurie, Cecelia A., Rotter, Jerome I., Vasan, Ramachandran S., Post, Wendy S., Peyser, Patricia A., Miller, Clint L., and Malhotra, Rajeev

Published
2023
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6. Semi-automated assembly of high-quality diploid human reference genomes

Author

Jarvis, Erich D, Formenti, Giulio, Rhie, Arang, Guarracino, Andrea, Yang, Chentao, Wood, Jonathan, Tracey, Alan, Thibaud-Nissen, Francoise, Vollger, Mitchell R, Porubsky, David, Cheng, Haoyu, Asri, Mobin, Logsdon, Glennis A, Carnevali, Paolo, Chaisson, Mark JP, Chin, Chen-Shan, Cody, Sarah, Collins, Joanna, Ebert, Peter, Escalona, Merly, Fedrigo, Olivier, Fulton, Robert S, Fulton, Lucinda L, Garg, Shilpa, Gerton, Jennifer L, Ghurye, Jay, Granat, Anastasiya, Green, Richard E, Harvey, William, Hasenfeld, Patrick, Hastie, Alex, Haukness, Marina, Jaeger, Erich B, Jain, Miten, Kirsche, Melanie, Kolmogorov, Mikhail, Korbel, Jan O, Koren, Sergey, Korlach, Jonas, Lee, Joyce, Li, Daofeng, Lindsay, Tina, Lucas, Julian, Luo, Feng, Marschall, Tobias, Mitchell, Matthew W, McDaniel, Jennifer, Nie, Fan, Olsen, Hugh E, Olson, Nathan D, Pesout, Trevor, Potapova, Tamara, Puiu, Daniela, Regier, Allison, Ruan, Jue, Salzberg, Steven L, Sanders, Ashley D, Schatz, Michael C, Schmitt, Anthony, Schneider, Valerie A, Selvaraj, Siddarth, Shafin, Kishwar, Shumate, Alaina, Stitziel, Nathan O, Stober, Catherine, Torrance, James, Wagner, Justin, Wang, Jianxin, Wenger, Aaron, Xiao, Chuanle, Zimin, Aleksey V, Zhang, Guojie, Wang, Ting, Li, Heng, Garrison, Erik, Haussler, David, Hall, Ira, Zook, Justin M, Eichler, Evan E, Phillippy, Adam M, Paten, Benedict, Howe, Kerstin, and Miga, Karen H

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Generic health relevance, Humans, Chromosome Mapping, Diploidy, Genome, Human, Haplotypes, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Reference Standards, Genomics, Chromosomes, Human, Genetic Variation, Human Pangenome Reference Consortium, General Science & Technology
Abstract

The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society1,2. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals3,4. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome5. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity6. Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent-child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements.

Published
2022

7. Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Author

Yin, Xianyong, Bose, Debraj, Kwon, Annie, Hanks, Sarah C, Jackson, Anne U, Stringham, Heather M, Welch, Ryan, Oravilahti, Anniina, Silva, Lilian Fernandes, FinnGen, Locke, Adam E, Fuchsberger, Christian, Service, Susan K, Erdos, Michael R, Bonnycastle, Lori L, Kuusisto, Johanna, Stitziel, Nathan O, Hall, Ira M, Morrison, Jean, Ripatti, Samuli, Palotie, Aarno, Freimer, Nelson B, Collins, Francis S, Mohlke, Karen L, Scott, Laura J, Fauman, Eric B, Burant, Charles, Boehnke, Michael, Laakso, Markku, and Wen, Xiaoquan

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Medical Biochemistry and Metabolomics, Nutrition, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Bilirubin, Carnitine, Genome-Wide Association Study, Glycerophospholipids, Humans, Male, Metabolomics, Quantitative Trait Loci, Solute Carrier Family 22 Member 5, Transcriptome, FinnGen, colocalizataion, genome-wide association study, metabolomics, transcriptome-wide association study, transcriptomics, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology.

Published
2022

10. Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Author

Yin, Xianyong, Chan, Lap Sum, Bose, Debraj, Jackson, Anne U, VandeHaar, Peter, Locke, Adam E, Fuchsberger, Christian, Stringham, Heather M, Welch, Ryan, Yu, Ketian, Fernandes Silva, Lilian, Service, Susan K, Zhang, Daiwei, Hector, Emily C, Young, Erica, Ganel, Liron, Das, Indraniel, Abel, Haley, Erdos, Michael R, Bonnycastle, Lori L, Kuusisto, Johanna, Stitziel, Nathan O, Hall, Ira M, Wagner, Gregory R, Kang, Jian, Morrison, Jean, Burant, Charles F, Collins, Francis S, Ripatti, Samuli, Palotie, Aarno, Freimer, Nelson B, Mohlke, Karen L, Scott, Laura J, Wen, Xiaoquan, Fauman, Eric B, Laakso, Markku, and Boehnke, Michael

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Medical Biochemistry and Metabolomics, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Alleles, Finland, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Phenotype, Polymorphism, Single Nucleotide, FinnGen
Abstract

Few studies have explored the impact of rare variants (minor allele frequency

Published
2022

11. Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences

Author

Ganel, Liron, Chen, Lei, Christ, Ryan, Vangipurapu, Jagadish, Young, Erica, Das, Indraniel, Kanchi, Krishna, Larson, David, Regier, Allison, Abel, Haley, Kang, Chul Joo, Scott, Alexandra, Havulinna, Aki, Chiang, Charleston WK, Service, Susan, Freimer, Nelson, Palotie, Aarno, Ripatti, Samuli, Kuusisto, Johanna, Boehnke, Michael, Laakso, Markku, Locke, Adam, Stitziel, Nathan O, and Hall, Ira M

Subjects
Biological Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Adult, Aged, Apoptosis Regulatory Proteins, Cell Lineage, DNA Copy Number Variations, DNA, Mitochondrial, Female, GTP-Binding Proteins, Genetic Predisposition to Disease, Genome, Mitochondrial, Genome-Wide Association Study, Humans, Male, Membrane Proteins, Mendelian Randomization Analysis, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-myb, Sequence Analysis, DNA, Exome Sequencing, Metabolic syndrome, Mitochondrial content, Human genetics, Human genome sequencing, Genome-wide association studies, Mendelian randomization, Genetics & Heredity, Biochemistry and cell biology
Abstract

BackgroundMitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718).ResultsWe identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 × 10-8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 × 10-8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 × 10-21) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition.ConclusionThese results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.

Published
2021

14. SVEP1 is an endogenous ligand for the orphan receptor PEAR1

Author

Elenbaas, Jared S., Pudupakkam, Upasana, Ashworth, Katrina J., Kang, Chul Joo, Patel, Ved, Santana, Katherine, Jung, In-Hyuk, Lee, Paul C., Burks, Kendall H., Amrute, Junedh M., Mecham, Robert P., Halabi, Carmen M., Alisio, Arturo, Di Paola, Jorge, and Stitziel, Nathan O.

Published
2023
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17. Association of structural variation with cardiometabolic traits in Finns

Author

Chen, Lei, Abel, Haley J, Das, Indraniel, Larson, David E, Ganel, Liron, Kanchi, Krishna L, Regier, Allison A, Young, Erica P, Kang, Chul Joo, Scott, Alexandra J, Chiang, Colby, Wang, Xinxin, Lu, Shuangjia, Christ, Ryan, Service, Susan K, Chiang, Charleston WK, Havulinna, Aki S, Kuusisto, Johanna, Boehnke, Michael, Laakso, Markku, Palotie, Aarno, Ripatti, Samuli, Freimer, Nelson B, Locke, Adam E, Stitziel, Nathan O, and Hall, Ira M

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Alleles, Cardiovascular Diseases, Cholesterol, DNA Copy Number Variations, Female, Finland, Genome, Human, Genomic Structural Variation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Promoter Regions, Genetic, Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Pyruvic Acid, Serum Albumin, Human, Finnish population, cardiometabolic traits, genome-wide association study, structural variation, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47 × 10-54) and is also associated with increased levels of total cholesterol (p = 1.22 × 10-28) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81 × 10-21) and alanine (p = 6.14 × 10-12) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24 × 10-10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53 × 10-35). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

Published
2021

19. Mapping and characterization of structural variation in 17,795 human genomes

Author

Abel, Haley J, Larson, David E, Regier, Allison A, Chiang, Colby, Das, Indraniel, Kanchi, Krishna L, Layer, Ryan M, Neale, Benjamin M, Salerno, William J, Reeves, Catherine, Buyske, Steven, Matise, Tara C, Muzny, Donna M, Zody, Michael C, Lander, Eric S, Dutcher, Susan K, Stitziel, Nathan O, and Hall, Ira M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Generic health relevance, Alleles, Case-Control Studies, Epigenesis, Genetic, Female, Gene Dosage, Genetic Variation, Genetics, Population, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Molecular Sequence Annotation, Quantitative Trait Loci, Racial Groups, Software, Whole Genome Sequencing, NHGRI Centers for Common Disease Genomics, General Science & Technology
Abstract

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.

Published
2020

21. Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury

Author

Guo, Zhen, Valenzuela Ripoll, Carla, Picataggi, Antonino, Rawnsley, David R., Ozcan, Mualla, Chirinos, Julio A., Chendamarai, Ezhilarasi, Girardi, Amanda, Riehl, Terrence, Evie, Hosannah, Diab, Ahmed, Kovacs, Attila, Hyrc, Krzysztof, Ma, Xiucui, Asnani, Aarti, Shewale, Swapnil V., Scherrer-Crosbie, Marielle, Cowart, Lauren Ashley, Parks, John S., Zhao, Lei, Gordon, David, Ramirez-Valle, Francisco, Margulies, Kenneth B., Cappola, Thomas P., Desai, Ankit A., Pedersen, Lauren N., Bergom, Carmen, Stitziel, Nathan O., Rettig, Michael P., DiPersio, John F., Hajny, Stefan, Christoffersen, Christina, Diwan, Abhinav, and Javaheri, Ali

Published
2023
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23. Genetic architecture of human plasma lipidome and its link to cardiovascular disease.

Author

Tabassum, Rubina, Rämö, Joel T, Ripatti, Pietari, Koskela, Jukka T, Kurki, Mitja, Karjalainen, Juha, Palta, Priit, Hassan, Shabbeer, Nunez-Fontarnau, Javier, Kiiskinen, Tuomo TJ, Söderlund, Sanni, Matikainen, Niina, Gerl, Mathias J, Surma, Michal A, Klose, Christian, Stitziel, Nathan O, Laivuori, Hannele, Havulinna, Aki S, Service, Susan K, Salomaa, Veikko, Pirinen, Matti, FinnGen Project, Jauhiainen, Matti, Daly, Mark J, Freimer, Nelson B, Palotie, Aarno, Taskinen, Marja-Riitta, Simons, Kai, and Ripatti, Samuli

Subjects
FinnGen Project, Plasma, Humans, Cardiovascular Diseases, Lipids, Genome-Wide Association Study, Lipidomics
Abstract

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P

Published
2019

24. Exome sequencing of Finnish isolates enhances rare-variant association power

Author

Locke, Adam E, Steinberg, Karyn Meltz, Chiang, Charleston WK, Service, Susan K, Havulinna, Aki S, Stell, Laurel, Pirinen, Matti, Abel, Haley J, Chiang, Colby C, Fulton, Robert S, Jackson, Anne U, Kang, Chul Joo, Kanchi, Krishna L, Koboldt, Daniel C, Larson, David E, Nelson, Joanne, Nicholas, Thomas J, Pietilä, Arto, Ramensky, Vasily, Ray, Debashree, Scott, Laura J, Stringham, Heather M, Vangipurapu, Jagadish, Welch, Ryan, Yajnik, Pranav, Yin, Xianyong, Eriksson, Johan G, Ala-Korpela, Mika, Järvelin, Marjo-Riitta, Männikkö, Minna, Laivuori, Hannele, Dutcher, Susan K, Stitziel, Nathan O, Wilson, Richard K, Hall, Ira M, Sabatti, Chiara, Palotie, Aarno, Salomaa, Veikko, Laakso, Markku, Ripatti, Samuli, Boehnke, Michael, and Freimer, Nelson B

Subjects
Medical Biochemistry and Metabolomics, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Alleles, Cholesterol, HDL, Cluster Analysis, Endpoint Determination, Finland, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Geographic Mapping, Humans, Multifactorial Inheritance, Quantitative Trait Loci, Reproducibility of Results, Exome Sequencing, FinnGen Project, General Science & Technology
Abstract

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

Published
2019

25. Coronary Artery Disease Risk and Lipidomic Profiles Are Similar in Hyperlipidemias With Family History and Population‐Ascertained Hyperlipidemias

Author

Rämö, Joel T, Ripatti, Pietari, Tabassum, Rubina, Söderlund, Sanni, Matikainen, Niina, Gerl, Mathias J, Klose, Christian, Surma, Michal A, Stitziel, Nathan O, Havulinna, Aki S, Pirinen, Matti, Salomaa, Veikko, Freimer, Nelson B, Jauhiainen, Matti, Palotie, Aarno, Taskinen, Marja‐Riitta, Simons, Kai, and Ripatti, Samuli

Subjects
Atherosclerosis, Digestive Diseases, Heart Disease, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Adult, Cholesterol, LDL, Coronary Artery Disease, Family, Female, Finland, Humans, Hypercholesterolemia, Hyperlipidemias, Hypertriglyceridemia, Lipidomics, Male, Medical History Taking, Middle Aged, Proportional Hazards Models, Triglycerides, coronary artery disease, family study, high-risk populations, hypercholesterolemia, hypertriglyceridemia, lipids and lipoproteins, high‐risk populations, Cardiorespiratory Medicine and Haematology
Abstract

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low-density lipoprotein cholesterol ( LDL -C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population-based hyperlipidemias. Methods and Results We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first-degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias ( LDL -C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta-analysis of the hyperlipidemic families and the population cohort (high LDL -C: hazard ratio, 1.74 [95% CI, 1.48-2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09-1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid-lowering medication. In lipidomic profiling, high LDL -C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P-value range 0.038-2.3×10-56). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population ( LDL -C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts). Conclusions Hyperlipidemias with family history conferred similar coronary artery disease risk as population-based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL -C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

Published
2019

27. ANGPTL3 Deficiency and Risk of Hepatic Steatosis

Author

D’Erasmo, Laura, Di Martino, Michele, Neufeld, Thomas, Fraum, Tyler J., Kang, Chul Joo, Burks, Kendall H., Di Costanzo, Alessia, Minicocci, Ilenia, Bini, Simone, Maranghi, Marianna, Pigna, Giovanni, Labbadia, Giancarlo, Zheng, Jie, Fierro, Davide, Montali, Anna, Ceci, Fabrizio, Catalano, Carlo, Davidson, Nicholas O., Lucisano, Giuseppe, Nicolucci, Antonio, Arca, Marcello, and Stitziel, Nathan O.

Published
2023
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28. Decoding the Therapeutic Target SVEP1: Harnessing Molecular Trait GWASs to Unravel Mechanisms of Human Disease.

Author

Elenbaas, Jared S., Lee, Paul C., Patel, Ved, and Stitziel, Nathan O.

Subjects
GENOME-wide association studies, GLAUCOMA, CELLULAR signal transduction, CORONARY artery disease, CELL receptors, GENETICS
Abstract

Although human genetics has substantial potential to illuminate novel disease pathways and facilitate drug development, identifying causal variants and deciphering their mechanisms remain challenging. We believe these challenges can be addressed, in part, by creatively repurposing the results of molecular trait genome-wide association studies (GWASs). In this review, we introduce techniques related to molecular GWASs and unconventionally apply them to understanding SVEP1, a human coronary artery disease risk locus. Our analyses highlight SVEP1's causal link to cardiometabolic disease and glaucoma, as well as the surprising discovery of SVEP1 as the first known physiologic ligand for PEAR1, a critical receptor governing platelet reactivity. We further employ these techniques to dissect the interactions between SVEP1, PEAR1, and the Ang/Tie pathway, with therapeutic implications for a constellation of diseases. This review underscores the potential of molecular GWASs to guide drug discovery and unravel the complexities of human health and disease by demonstrating an integrative approach that grounds mechanistic research in human biology. [ABSTRACT FROM AUTHOR]

Published
2025
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29. An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery

Author

Haghighi, Alireza, Krier, Joel B, Toth-Petroczy, Agnes, Cassa, Christopher A, Frank, Natasha Y, Carmichael, Nikkola, Fieg, Elizabeth, Bjonnes, Andrew, Mohanty, Anwoy, Briere, Lauren C, Lincoln, Sharyn, Lucia, Stephanie, Gupta, Vandana A, Söylemez, Onuralp, Sutti, Sheila, Kooshesh, Kameron, Qiu, Haiyan, Fay, Christopher J, Perroni, Victoria, Valerius, Jamie, Hanna, Meredith, Frank, Alexander, Ouahed, Jodie, Snapper, Scott B, Pantazi, Angeliki, Chopra, Sameer S, Leshchiner, Ignaty, Stitziel, Nathan O, Feldweg, Anna, Mannstadt, Michael, Loscalzo, Joseph, Sweetser, David A, Liao, Eric, Stoler, Joan M, Nowak, Catherine B, Sanchez-Lara, Pedro A, Klein, Ophir D, Perry, Hazel, Patsopoulos, Nikolaos A, Raychaudhuri, Soumya, Goessling, Wolfram, Green, Robert C, Seidman, Christine E, MacRae, Calum A, Sunyaev, Shamil R, Maas, Richard L, Vuzman, Dana, and Undiagnosed Diseases Network, Brigham and Women’s Hospital FaceBase Project, Brigham Genomic Medicine (BGM)

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Biotechnology, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Undiagnosed Diseases Network, Brigham and Women’s Hospital FaceBase Project, Brigham Genomic Medicine, Medical biotechnology
Abstract

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

Published
2018

32. Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Author

Natarajan, Pradeep, Bis, Joshua C, Bielak, Lawrence F, Cox, Amanda J, Dörr, Marcus, Feitosa, Mary F, Franceschini, Nora, Guo, Xiuqing, Hwang, Shih-Jen, Isaacs, Aaron, Jhun, Min A, Kavousi, Maryam, Li-Gao, Ruifang, Lyytikäinen, Leo-Pekka, Marioni, Riccardo E, Schminke, Ulf, Stitziel, Nathan O, Tada, Hayato, van Setten, Jessica, Smith, Albert V, Vojinovic, Dina, Yanek, Lisa R, Yao, Jie, Yerges-Armstrong, Laura M, Amin, Najaf, Baber, Usman, Borecki, Ingrid B, Carr, J Jeffrey, Chen, Yii-Der Ida, Cupples, L Adrienne, de Jong, Pim A, de Koning, Harry, de Vos, Bob D, Demirkan, Ayse, Fuster, Valentin, Franco, Oscar H, Goodarzi, Mark O, Harris, Tamara B, Heckbert, Susan R, Heiss, Gerardo, Hoffmann, Udo, Hofman, Albert, Išgum, Ivana, Jukema, J Wouter, Kähönen, Mika, Kardia, Sharon LR, Kral, Brian G, Launer, Lenore J, Massaro, Joe, Mehran, Roxana, Mitchell, Braxton D, Mosley, Thomas H, de Mutsert, Renée, Newman, Anne B, Nguyen, Khanh-Dung, North, Kari E, O'Connell, Jeffrey R, Oudkerk, Matthijs, Pankow, James S, Peloso, Gina M, Post, Wendy, Province, Michael A, Raffield, Laura M, Raitakari, Olli T, Reilly, Dermot F, Rivadeneira, Fernando, Rosendaal, Frits, Sartori, Samantha, Taylor, Kent D, Teumer, Alexander, Trompet, Stella, Turner, Stephen T, Uitterlinden, Andre G, Vaidya, Dhananjay, van der Lugt, Aad, Völker, Uwe, Wardlaw, Joanna M, Wassel, Christina L, Weiss, Stefan, Wojczynski, Mary K, Becker, Diane M, Becker, Lewis C, Boerwinkle, Eric, Bowden, Donald W, Deary, Ian J, Dehghan, Abbas, Felix, Stephan B, Gudnason, Vilmundur, Lehtimäki, Terho, Mathias, Rasika, Mook-Kanamori, Dennis O, Psaty, Bruce M, Rader, Daniel J, Rotter, Jerome I, Wilson, James G, van Duijn, Cornelia M, Völzke, Henry, Kathiresan, Sekar, Peyser, Patricia A, and O'Donnell, Christopher J

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Atherosclerosis, Genetics, Heart Disease, Prevention, Aging, Heart Disease - Coronary Heart Disease, Human Genome, Cardiovascular, Good Health and Well Being, Apolipoprotein B-100, Apolipoprotein E2, Asymptomatic Diseases, Black People, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cholesterol, LDL, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Exome, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Odds Ratio, Oligonucleotide Array Sequence Analysis, Phenotype, Prognosis, Risk Assessment, Risk Factors, Vascular Calcification, White People, carotid intima-media thickness, coronary artery calcification, exome, genome-wide association study, genomics, CHARGE Consortium, carotid intima–media thickness, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThe burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.Methods and resultsWe studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10-10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10-12) and 1.4% reduced carotid intima-media thickness (P=4×10-14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10-11).ConclusionsExome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Published
2016

33. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author

Liu, Chunyu, Kraja, Aldi T, Smith, Jennifer A, Brody, Jennifer A, Franceschini, Nora, Bis, Joshua C, Rice, Kenneth, Morrison, Alanna C, Lu, Yingchang, Weiss, Stefan, Guo, Xiuqing, Palmas, Walter, Martin, Lisa W, Chen, Yii-Der Ida, Surendran, Praveen, Drenos, Fotios, Cook, James P, Auer, Paul L, Chu, Audrey Y, Giri, Ayush, Zhao, Wei, Jakobsdottir, Johanna, Lin, Li-An, Stafford, Jeanette M, Amin, Najaf, Mei, Hao, Yao, Jie, Voorman, Arend, Larson, Martin G, Grove, Megan L, Smith, Albert V, Hwang, Shih-Jen, Chen, Han, Huan, Tianxiao, Kosova, Gulum, Stitziel, Nathan O, Kathiresan, Sekar, Samani, Nilesh, Schunkert, Heribert, Deloukas, Panos, Li, Man, Fuchsberger, Christian, Pattaro, Cristian, Gorski, Mathias, Kooperberg, Charles, Papanicolaou, George J, Rossouw, Jacques E, Faul, Jessica D, Kardia, Sharon LR, Bouchard, Claude, Raffel, Leslie J, Uitterlinden, André G, Franco, Oscar H, Vasan, Ramachandran S, O'Donnell, Christopher J, Taylor, Kent D, Liu, Kiang, Bottinger, Erwin P, Gottesman, Omri, Daw, E Warwick, Giulianini, Franco, Ganesh, Santhi, Salfati, Elias, Harris, Tamara B, Launer, Lenore J, Dörr, Marcus, Felix, Stephan B, Rettig, Rainer, Völzke, Henry, Kim, Eric, Lee, Wen-Jane, Lee, I-Te, Sheu, Wayne H-H, Tsosie, Krystal S, Edwards, Digna R Velez, Liu, Yongmei, Correa, Adolfo, Weir, David R, Völker, Uwe, Ridker, Paul M, Boerwinkle, Eric, Gudnason, Vilmundur, Reiner, Alexander P, van Duijn, Cornelia M, Borecki, Ingrid B, Edwards, Todd L, Chakravarti, Aravinda, Rotter, Jerome I, Psaty, Bruce M, Loos, Ruth JF, Fornage, Myriam, Ehret, Georg B, Newton-Cheh, Christopher, Levy, Daniel, and Chasman, Daniel I

Subjects
Biological Sciences, Genetics, Prevention, Hypertension, Cardiovascular, 2.1 Biological and endogenous factors, Blood Pressure, Exome, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, CHD Exome+ Consortium, ExomeBP Consortium, GoT2DGenes Consortium, T2D-GENES Consortium, Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia, CKDGen Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Published
2016

34. Reducing the Risk of Pancreatitis by Inhibiting APOC3.

Author

Stitziel, Nathan O.

Subjects
*METABOLIC disorders, *APOLIPOPROTEIN C, *LIPOPROTEINS, *HYPERTRIGLYCERIDEMIA, *PANCREATITIS
Abstract

The article discusses the risk of pancreatitis in patients with extreme hypertriglyceridemia and the potential benefits of inhibiting APOC3 to reduce this risk. It highlights the efficacy of plozasiran in lowering plasma APOC3 levels and triglyceride levels, thereby reducing the risk of pancreatitis in patients with familial chylomicronemia syndrome (FCS). The study suggests that targeting APOC3 may be a useful therapy for reducing the risk of high triglyceride levels and pancreatitis in related conditions, such as treatment-refractory MCS. The findings provide evidence that inhibiting APOC3 can effectively reduce the risk of pancreatitis in patients with FCS, offering a promising path forward for managing extreme hypertriglyceridemia and mitigating the risk of pancreatitis. [Extracted from the article]

Published
2025
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35. Exome Sequencing in Suspected Monogenic Dyslipidemias

Author

Stitziel, Nathan O, Peloso, Gina M, Abifadel, Marianne, Cefalu, Angelo B, Fouchier, Sigrid, Motazacker, M Mahdi, Tada, Hayato, Larach, Daniel B, Awan, Zuhier, Haller, Jorge F, Pullinger, Clive R, Varret, Mathilde, Rabès, Jean-Pierre, Noto, Davide, Tarugi, Patrizia, Kawashiri, Masa-Aki, Nohara, Atsushi, Yamagishi, Masakazu, Risman, Marjorie, Deo, Rahul, Ruel, Isabelle, Shendure, Jay, Nickerson, Deborah A, Wilson, James G, Rich, Stephen S, Gupta, Namrata, Farlow, Deborah N, Neale, Benjamin M, Daly, Mark J, Kane, John P, Freeman, Mason W, Genest, Jacques, Rader, Daniel J, Mabuchi, Hiroshi, Kastelein, John JP, Hovingh, G Kees, Averna, Maurizio R, Gabriel, Stacey, Boileau, Catherine, and Kathiresan, Sekar

Subjects
Clinical Research, Human Genome, Atherosclerosis, Genetics, Aetiology, 2.1 Biological and endogenous factors, Dyslipidemias, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Metabolism, Inborn Errors, DNA sequencing, exome, genetics, human, lipids, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology
Abstract

BackgroundExome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias.Methods and resultsWe performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease.ConclusionsWe identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.

Published
2015

36. Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease

Author

Stitziel, Nathan O, Won, Hong-Hee, Morrison, Alanna C, Peloso, Gina M, Do, Ron, Lange, Leslie A, Fontanillas, Pierre, Gupta, Namrata, Duga, Stefano, Goel, Anuj, Farrall, Martin, Saleheen, Danish, Ferrario, Paola, König, Inke, Asselta, Rosanna, Merlini, Piera A, Marziliano, Nicola, Notarangelo, Maria Francesca, Schick, Ursula, Auer, Paul, Assimes, Themistocles L, Reilly, Muredach, Wilensky, Robert, Rader, Daniel J, Hovingh, G Kees, Meitinger, Thomas, Kessler, Thorsten, Kastrati, Adnan, Laugwitz, Karl-Ludwig, Siscovick, David, Rotter, Jerome I, Hazen, Stanely L, Tracy, Russell, Cresci, Sharon, Spertus, John, Jackson, Rebecca, Schwartz, Stephen M, Natarajan, Pradeep, Crosby, Jacy, Muzny, Donna, Ballantyne, Christie, Rich, Stephen S, O'Donnell, Christopher J, Abecasis, Goncalo, Sunaev, Shamil, Nickerson, Deborah A, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Austin, Erin, Kullo, Iftikhar J, Weeke, Peter E, Shaffer, Christian M, Bastarache, Lisa A, Denny, Joshua C, Roden, Dan M, Palmer, Colin, Deloukas, Panos, Lin, Dan-Yu, Tang, Zheng-zheng, Erdmann, Jeanette, Schunkert, Heribert, Danesh, John, Marrugat, Jaume, Elosua, Roberto, Ardissino, Diego, McPherson, Ruth, Watkins, Hugh, Reiner, Alex P, Wilson, James G, Altshuler, David, Gibbs, Richard A, Lander, Eric S, Boerwinkle, Eric, Gabriel, Stacey, and Kathiresan, Sekar

Subjects
Biomedical and Clinical Sciences, Cardiovascular, Atherosclerosis, Heart Disease, Genetics, Heart Disease - Coronary Heart Disease, 5.1 Pharmaceuticals, Adult, Asian People, Black People, Case-Control Studies, Cholesterol, LDL, Coronary Disease, Exons, Female, Gene Silencing, Genotype, Humans, Male, Membrane Proteins, Membrane Transport Proteins, Middle Aged, Mutation, Protein Conformation, Risk, Sequence Analysis, DNA, Triglycerides, White People, Myocardial Infarction Genetics Consortium Investigators, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundEzetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug.MethodsWe sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease.ResultsWith sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%).ConclusionsNaturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).

Published
2014

37. Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Author

Lim, Elaine T, Würtz, Peter, Havulinna, Aki S, Palta, Priit, Tukiainen, Taru, Rehnström, Karola, Esko, Tõnu, Mägi, Reedik, Inouye, Michael, Lappalainen, Tuuli, Chan, Yingleong, Salem, Rany M, Lek, Monkol, Flannick, Jason, Sim, Xueling, Manning, Alisa, Ladenvall, Claes, Bumpstead, Suzannah, Hämäläinen, Eija, Aalto, Kristiina, Maksimow, Mikael, Salmi, Marko, Blankenberg, Stefan, Ardissino, Diego, Shah, Svati, Horne, Benjamin, McPherson, Ruth, Hovingh, Gerald K, Reilly, Muredach P, Watkins, Hugh, Goel, Anuj, Farrall, Martin, Girelli, Domenico, Reiner, Alex P, Stitziel, Nathan O, Kathiresan, Sekar, Gabriel, Stacey, Barrett, Jeffrey C, Lehtimäki, Terho, Laakso, Markku, Groop, Leif, Kaprio, Jaakko, Perola, Markus, McCarthy, Mark I, Boehnke, Michael, Altshuler, David M, Lindgren, Cecilia M, Hirschhorn, Joel N, Metspalu, Andres, Freimer, Nelson B, Zeller, Tanja, Jalkanen, Sirpa, Koskinen, Seppo, Raitakari, Olli, Durbin, Richard, MacArthur, Daniel G, Salomaa, Veikko, Ripatti, Samuli, Daly, Mark J, Palotie, Aarno, and Sequencing Initiative Suomi (SISu) Project

Subjects
Sequencing Initiative Suomi (SISu) Project, Humans, Genetic Diseases, Inborn, Genetics, Population, Founder Effect, Gene Frequency, Genetic Drift, Phenotype, European Continental Ancestry Group, Finland, Female, Male, Genetic Variation, Genome-Wide Association Study, Exome, Genetics, Human Genome, 2.1 Biological and endogenous factors, Generic health relevance, Cardiovascular, Developmental Biology
Abstract

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p

Published
2014

39. Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

Author

Peloso, Gina M, Auer, Paul L, Bis, Joshua C, Voorman, Arend, Morrison, Alanna C, Stitziel, Nathan O, Brody, Jennifer A, Khetarpal, Sumeet A, Crosby, Jacy R, Fornage, Myriam, Isaacs, Aaron, Jakobsdottir, Johanna, Feitosa, Mary F, Davies, Gail, Huffman, Jennifer E, Manichaikul, Ani, Davis, Brian, Lohman, Kurt, Joon, Aron Y, Smith, Albert V, Grove, Megan L, Zanoni, Paolo, Redon, Valeska, Demissie, Serkalem, Lawson, Kim, Peters, Ulrike, Carlson, Christopher, Jackson, Rebecca D, Ryckman, Kelli K, Mackey, Rachel H, Robinson, Jennifer G, Siscovick, David S, Schreiner, Pamela J, Mychaleckyj, Josyf C, Pankow, James S, Hofman, Albert, Uitterlinden, Andre G, Harris, Tamara B, Taylor, Kent D, Stafford, Jeanette M, Reynolds, Lindsay M, Marioni, Riccardo E, Dehghan, Abbas, Franco, Oscar H, Patel, Aniruddh P, Lu, Yingchang, Hindy, George, Gottesman, Omri, Bottinger, Erwin P, Melander, Olle, Orho-Melander, Marju, Loos, Ruth JF, Duga, Stefano, Merlini, Piera Angelica, Farrall, Martin, Goel, Anuj, Asselta, Rosanna, Girelli, Domenico, Martinelli, Nicola, Shah, Svati H, Kraus, William E, Li, Mingyao, Rader, Daniel J, Reilly, Muredach P, McPherson, Ruth, Watkins, Hugh, Ardissino, Diego, Project, NHLBI GO Exome Sequencing, Zhang, Qunyuan, Wang, Judy, Tsai, Michael Y, Taylor, Herman A, Correa, Adolfo, Griswold, Michael E, Lange, Leslie A, Starr, John M, Rudan, Igor, Eiriksdottir, Gudny, Launer, Lenore J, Ordovas, Jose M, Levy, Daniel, Chen, Y-D Ida, Reiner, Alexander P, Hayward, Caroline, Polasek, Ozren, Deary, Ian J, Borecki, Ingrid B, Liu, Yongmei, Gudnason, Vilmundur, Wilson, James G, van Duijn, Cornelia M, Kooperberg, Charles, Rich, Stephen S, Psaty, Bruce M, Rotter, Jerome I, O’Donnell, Christopher J, Rice, Kenneth, Boerwinkle, Eric, Kathiresan, Sekar, and Cupples, L Adrienne

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Cardiovascular, Heart Disease, Clinical Research, Atherosclerosis, Heart Disease - Coronary Heart Disease, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Adult, Aged, Alleles, Animals, Black People, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Coronary Disease, Female, Gene Frequency, Genetic Association Studies, Genetic Code, Genetic Variation, Humans, Linear Models, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins, Middle Aged, Phenotype, Sequence Analysis, DNA, Subtilisins, Triglycerides, White People, NHLBI GO Exome Sequencing Project, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Published
2014

40. Roadmap for a precision-medicine initiative in the Nordic region

Author

Njølstad, Pål Rasmus, Andreassen, Ole Andreas, Brunak, Søren, Børglum, Anders D., Dillner, Joakim, Esko, Tõnu, Franks, Paul W., Freimer, Nelson, Groop, Leif, Heimer, Hakon, Hougaard, David M., Hovig, Eivind, Hveem, Kristian, Jalanko, Anu, Kaprio, Jaakko, Knudsen, Gun Peggy, Melbye, Mads, Metspalu, Andres, Mortensen, Preben Bo, Palmgren, Juni, Palotie, Aarno, Reed, Wenche, Stefánsson, Hreinn, Stitziel, Nathan O., Sullivan, Patrick F., Thorsteinsdóttir, Unnur, Vaudel, Marc, Vuorio, Eero, Werge, Thomas, Stoltenberg, Camilla, and Stefánsson, Kári

Published
2019
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45. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Author

Zanoni, Paolo, Khetarpal, Sumeet A., Larach, Daniel B., Hancock-Cerutti, William F., Millar, John S., Cuchel, Marina, DerOhannessian, Stephanie, Kontush, Anatol, Surendran, Praveen, Saleheen, Danish, Trompet, Stella, Jukema, J. Wouter, De Craen, Anton, Deloukas, Panos, Sattar, Naveed, Ford, Ian, Packard, Chris, Majumder, Abdullah al Shafi, Alam, Dewan S., Di Angelantonio, Emanuele, Abecasis, Goncalo, Chowdhury, Rajiv, Erdmann, Jeanette, Nordestgaard, Børge G., Nielsen, Sune F., Tybjærg-Hansen, Anne, Schmidt, Ruth Frikke, Kuulasmaa, Kari, Liu, Dajiang J., Perola, Markus, Blankenberg, Stefan, Salomaa, Veikko, Männistö, Satu, Amouyel, Philippe, Arveiler, Dominique, Ferrieres, Jean, Müller-Nurasyid, Martina, Ferrario, Marco, Kee, Frank, Willer, Cristen J., Samani, Nilesh, Schunkert, Heribert, Butterworth, Adam S., Howson, Joanna M. M., Peloso, Gina M., Stitziel, Nathan O., Danesh, John, Kathiresan, Sekar, and Rader, Daniel J.

Published
2016

46. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials

Author

Mega, Jessica L, Stitziel, Nathan O, Smith, J Gustav, Chasman, Daniel I, Caulfield, Mark J, Devlin, James J, Nordio, Francesco, Hyde, Craig L, Cannon, Christopher P, Sacks, Frank M, Poulter, Neil R, Sever, Peter S, Ridker, Paul M, Braunwald, Eugene, Melander, Olle, Kathiresan, Sekar, and Sabatine, Marc S

Published
2015
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48. Supplement to: Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease.

Author

Stitziel, Nathan O., Stirrups, Kathleen E., Masca, Nicholas G.D., Erdmann, Jeanette, Ferrario, Paola G., König, Inke R., Weeke, Peter E., Webb, Thomas R., Auer, Paul L., Schick, Ursula M., Lu, Yingchang, Zhang, He, Dube, Marie-Pierre, Goel, Anuj, Farrall, Martin, Peloso, Gina M., Won, Hong-Hee, Do, Ron, van Iperen, Erik, Kanoni, Stavroula, Kruppa, Jochen, Mahajan, Anubha, Scott, Robert A., Willenborg, Christina, Braund, Peter S., van Capelleveen, Julian C., Doney, Alex S.F., Donnelly, Louise A., Asselta, Rosanna, Merlini, Piera A., Duga, Stefano, Marziliano, Nicola, Denny, Josh C., Shaffer, Christian M., El-Mokhtari, Nour Eddine, Franke, Andre, Gottesman, Omri, Heilmann, Stefanie, Hengstenberg, Christian, Hoffmann, Per, Holmen, Oddgeir L., Hveem, Kristian, Jansson, Jan-Håkan, Jöckel, Karl-Heinz, Kessler, Thorsten, Kriebel, Jennifer, Laugwitz, Karl L., Marouli, Eirini, Martinelli, Nicola, McCarthy, Mark I., Van Zuydam, Natalie R., Meisinger, Christa, Esko, Tõnu, Mihailov, Evelin, Escher, Stefan A., Alver, Maris, Moebus, Susanne, Morris, Andrew D., Müller-Nurasyid, Martina, Nikpay, Majid, Olivieri, Oliviero, Perreault, Louis-Philippe Lemieux, AlQarawi, Alaa, Robertson, Neil R., Akinsanya, Karen O., Reilly, Dermot F., Vogt, Thomas F., Yin, Wu, Asselbergs, Folkert W., Kooperberg, Charles, Jackson, Rebecca D., Stahl, Eli, Strauch, Konstantin, Varga, Tibor V., Waldenberger, Melanie, Zeng, Lingyao, Kraja, Aldi T., Liu, Chunyu, Ehret, Georg B., Newton-Cheh, Christopher, Chasman, Daniel I., Chowdhury, Rajiv, Ferrario, Marco, Ford, Ian, Jukema, Wouter J., Kee, Frank, Kuulasmaa, Kari, Nordestgaard, Børge G., Perola, Markus, Saleheen, Danish, Sattar, Naveed, Surendran, Praveen, Tregouet, David, Young, Robin, M. Howson, Joanna M., Butterworth, Adam S., Danesh, John, Ardissino, Diego, Bottinger, Erwin P., Erbel, Raimund, Franks, Paul W., Girelli, Domenico, Hall, Alistair S., Hovingh, Kees G., Kastrati, Adnan, Lieb, Wolfgang, Meitinger, Thomas, Kraus, William E., Shah, Svati H., McPherson, Ruth, Orho-Melander, Marju, Melander, Olle, Metspalu, Andres, Palmer, Colin N.A., Peters, Annette, Rader, Daniel J., Reilly, Muredach P., Loos, Ruth J.F., Reiner, Alex P., Roden, Dan M., Tardif, Jean-Claude, Thompson, John R., Wareham, Nicholas J., Watkins, Hugh, Willer, Cristen J., Kathiresan, Sekar, Deloukas, Panos, Samani, Nilesh J, and Schunkert, Heribert

Published
2016

49. Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling

Author

Emdin, Connor A., Khera, Amit V., Klarin, Derek, Natarajan, Pradeep, Zekavat, Seyedeh M., Nomura, Akihiro, Haas, Mary, Aragam, Krishna, Ardissino, Diego, Wilson, James G., Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J., Samani, Nilesh J., Baber, Usman, Erdmann, Jeanette, Gormley, Padhraig, Palotie, Aarno, Stitziel, Nathan O., Gupta, Namrata, Danesh, John, Saleheen, Danish, Gabriel, Stacey, and Kathiresan, Sekar

Published
2018
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