%0 Journal Article %J Am J Hum Genet %D 2021 %T Association of structural variation with cardiometabolic traits in Finns. %A Chen, Lei %A Abel, Haley J %A Das, Indraniel %A Larson, David E %A Ganel, Liron %A Kanchi, Krishna L %A Regier, Allison A %A Young, Erica P %A Kang, Chul Joo %A Scott, Alexandra J %A Chiang, Colby %A Wang, Xinxin %A Lu, Shuangjia %A Christ, Ryan %A Service, Susan K %A Chiang, Charleston W K %A Havulinna, Aki S %A Kuusisto, Johanna %A Boehnke, Michael %A Laakso, Markku %A Palotie, Aarno %A Ripatti, Samuli %A Freimer, Nelson B %A Locke, Adam E %A Stitziel, Nathan O %A Hall, Ira M %K Alleles %K Cardiovascular Diseases %K Cholesterol %K DNA Copy Number Variations %K Female %K Finland %K Genome, Human %K Genomic Structural Variation %K Genotype %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Mitochondrial Proteins %K Promoter Regions, Genetic %K Pyruvate Dehydrogenase (Lipoamide)-Phosphatase %K Pyruvic Acid %K Serum Albumin, Human %X

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) and is also associated with increased levels of total cholesterol (p = 1.22 × 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 × 10) and alanine (p = 6.14 × 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 × 10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53 × 10). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

%B Am J Hum Genet %V 108 %P 583-596 %8 2021 04 01 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33798444?dopt=Abstract %R 10.1016/j.ajhg.2021.03.008 %0 Journal Article %J Nature %D 2020 %T Mapping and characterization of structural variation in 17,795 human genomes. %A Abel, Haley J %A Larson, David E %A Regier, Allison A %A Chiang, Colby %A Das, Indraniel %A Kanchi, Krishna L %A Layer, Ryan M %A Neale, Benjamin M %A Salerno, William J %A Reeves, Catherine %A Buyske, Steven %A Matise, Tara C %A Muzny, Donna M %A Zody, Michael C %A Lander, Eric S %A Dutcher, Susan K %A Stitziel, Nathan O %A Hall, Ira M %K Alleles %K Case-Control Studies %K Continental Population Groups %K Epigenesis, Genetic %K Female %K Gene Dosage %K Genetic Variation %K Genetics, Population %K Genome, Human %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Molecular Sequence Annotation %K Quantitative Trait Loci %K Software %K Whole Genome Sequencing %X

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 pipeline 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.

%B Nature %V 583 %P 83-89 %8 2020 07 %G eng %N 7814 %1 https://www.ncbi.nlm.nih.gov/pubmed/32460305?dopt=Abstract %R 10.1038/s41586-020-2371-0