@article {151,
	title = {Association of structural variation with cardiometabolic traits in Finns.},
	journal = {Am J Hum Genet},
	volume = {108},
	year = {2021},
	month = {2021 04 01},
	pages = {583-596},
	abstract = {<p>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~{\texttimes} 10) and is also associated with increased levels of total cholesterol (p = 1.22~{\texttimes} 10) 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~{\texttimes} 10) and alanine (p = 6.14~{\texttimes} 10) 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~{\texttimes} 10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53~{\texttimes} 10). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.</p>},
	keywords = {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},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2021.03.008},
	author = {Chen, Lei and Abel, Haley J and Das, Indraniel and Larson, David E and Ganel, Liron and Kanchi, Krishna L and Regier, Allison A and Young, Erica P and Kang, Chul Joo and Scott, Alexandra J and Chiang, Colby and Wang, Xinxin and Lu, Shuangjia and Christ, Ryan and Service, Susan K and Chiang, Charleston W K and Havulinna, Aki S and Kuusisto, Johanna and Boehnke, Michael and Laakso, Markku and Palotie, Aarno and Ripatti, Samuli and Freimer, Nelson B and Locke, Adam E and Stitziel, Nathan O and Hall, Ira M}
}
@article {160,
	title = {SVEP1 is a human coronary artery disease locus that promotes atherosclerosis.},
	journal = {Sci Transl Med},
	volume = {13},
	year = {2021},
	month = {2021 Mar 24},
	abstract = {<p>A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1 and is further increased by the coronary disease-associated  variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Together, our results suggest that VSMC-derived SVEP1 is a proatherogenic factor and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.</p>},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.abe0357},
	author = {Jung, In-Hyuk and Elenbaas, Jared S and Alisio, Arturo and Santana, Katherine and Young, Erica P and Kang, Chul Joo and Kachroo, Puja and Lavine, Kory J and Razani, Babak and Mecham, Robert P and Stitziel, Nathan O}
}
