@article {8205, title = {Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {706-718}, abstract = {

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12\% in African-Americans, MAF = 2\% in Hispanics) lowered HbA1c (-0.88\% in hemizygous males, -0.34\% in heterozygous females) and explained 23\% of HbA1c variance in African-Americans and 4\% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5\%; -0.98\% in hemizygous males, -0.46\% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.08.010}, author = {Sarnowski, Chloe and Leong, Aaron and Raffield, Laura M and Wu, Peitao and de Vries, Paul S and DiCorpo, Daniel and Guo, Xiuqing and Xu, Huichun and Liu, Yongmei and Zheng, Xiuwen and Hu, Yao and Brody, Jennifer A and Goodarzi, Mark O and Hidalgo, Bertha A and Highland, Heather M and Jain, Deepti and Liu, Ching-Ti and Naik, Rakhi P and O{\textquoteright}Connell, Jeffrey R and Perry, James A and Porneala, Bianca C and Selvin, Elizabeth and Wessel, Jennifer and Psaty, Bruce M and Curran, Joanne E and Peralta, Juan M and Blangero, John and Kooperberg, Charles and Mathias, Rasika and Johnson, Andrew D and Reiner, Alexander P and Mitchell, Braxton D and Cupples, L Adrienne and Vasan, Ramachandran S and Correa, Adolfo and Morrison, Alanna C and Boerwinkle, Eric and Rotter, Jerome I and Rich, Stephen S and Manning, Alisa K and Dupuis, Jos{\'e}e and Meigs, James B} } @article {8621, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is~termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP~driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Francois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Goncalo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {8711, title = {Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 12}, pages = {2182}, abstract = {

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 {\texttimes} 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 {\texttimes} 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 {\texttimes} 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

}, issn = {2041-1723}, doi = {10.1038/s41467-021-22339-1}, author = {Natarajan, Pradeep and Pampana, Akhil and Graham, Sarah E and Ruotsalainen, Sanni E and Perry, James A and de Vries, Paul S and Broome, Jai G and Pirruccello, James P and Honigberg, Michael C and Aragam, Krishna and Wolford, Brooke and Brody, Jennifer A and Antonacci-Fulton, Lucinda and Arden, Moscati and Aslibekyan, Stella and Assimes, Themistocles L and Ballantyne, Christie M and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Do, Ron and Doddapaneni, Harsha and Emery, Leslie S and Hung, Yi-Jen and Irvin, Marguerite R and Khan, Alyna T and Lange, Leslie and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Metcalf, Ginger and Montasser, May E and Moon, Jee-Young and Muzny, Donna and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peralta, Juan M and Peyser, Patricia A and Stilp, Adrienne M and Tsai, Michael and Wang, Fei Fei and Weeks, Daniel E and Yanek, Lisa R and Wilson, James G and Abecasis, Goncalo and Arnett, Donna K and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Chang, Yi-Cheng and Chen, Yii-der I and Choi, Won Jung and Correa, Adolfo and Curran, Joanne E and Daly, Mark J and Dutcher, Susan K and Ellinor, Patrick T and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and He, Jiang and Hveem, Kristian and Jarvik, Gail P and Kaplan, Robert C and Kardia, Sharon L R and Kenny, Eimear and Kim, Ryan W and Kooperberg, Charles and Laurie, Cathy C and Lee, Seonwook and Lloyd-Jones, Don M and Loos, Ruth J F and Lubitz, Steven A and Mathias, Rasika A and Martinez, Karine A Viaud and McGarvey, Stephen T and Mitchell, Braxton D and Nickerson, Deborah A and North, Kari E and Palotie, Aarno and Park, Cheol Joo and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Seo, Daekwan and Seo, Jeong-Sun and Smith, Albert V and Tracy, Russell P and Vasan, Ramachandran S and Kathiresan, Sekar and Cupples, L Adrienne and Rotter, Jerome I and Morrison, Alanna C and Rich, Stephen S and Ripatti, Samuli and Willer, Cristen and Peloso, Gina M} } @article {8666, title = {Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.}, journal = {Nature}, volume = {590}, year = {2021}, month = {2021 02}, pages = {290-299}, abstract = {

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400~million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400~million detected variants, 97\% have frequencies of less than 1\% and 46\% are singletons that are present in only one individual (53\% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01\%.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03205-y}, author = {Taliun, Daniel and Harris, Daniel N and Kessler, Michael D and Carlson, Jedidiah and Szpiech, Zachary A and Torres, Raul and Taliun, Sarah A Gagliano and Corvelo, Andr{\'e} and Gogarten, Stephanie M and Kang, Hyun Min and Pitsillides, Achilleas N and LeFaive, Jonathon and Lee, Seung-Been and Tian, Xiaowen and Browning, Brian L and Das, Sayantan and Emde, Anne-Katrin and Clarke, Wayne E and Loesch, Douglas P and Shetty, Amol C and Blackwell, Thomas W and Smith, Albert V and Wong, Quenna and Liu, Xiaoming and Conomos, Matthew P and Bobo, Dean M and Aguet, Francois and Albert, Christine and Alonso, Alvaro and Ardlie, Kristin G and Arking, Dan E and Aslibekyan, Stella and Auer, Paul L and Barnard, John and Barr, R Graham and Barwick, Lucas and Becker, Lewis C and Beer, Rebecca L and Benjamin, Emelia J and Bielak, Lawrence F and Blangero, John and Boehnke, Michael and Bowden, Donald W and Brody, Jennifer A and Burchard, Esteban G and Cade, Brian E and Casella, James F and Chalazan, Brandon and Chasman, Daniel I and Chen, Yii-Der Ida and Cho, Michael H and Choi, Seung Hoan and Chung, Mina K and Clish, Clary B and Correa, Adolfo and Curran, Joanne E and Custer, Brian and Darbar, Dawood and Daya, Michelle and de Andrade, Mariza and DeMeo, Dawn L and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Eng, Celeste and Fatkin, Diane and Fingerlin, Tasha and Forer, Lukas and Fornage, Myriam and Franceschini, Nora and Fuchsberger, Christian and Fullerton, Stephanie M and Germer, Soren and Gladwin, Mark T and Gottlieb, Daniel J and Guo, Xiuqing and Hall, Michael E and He, Jiang and Heard-Costa, Nancy L and Heckbert, Susan R and Irvin, Marguerite R and Johnsen, Jill M and Johnson, Andrew D and Kaplan, Robert and Kardia, Sharon L R and Kelly, Tanika and Kelly, Shannon and Kenny, Eimear E and Kiel, Douglas P and Klemmer, Robert and Konkle, Barbara A and Kooperberg, Charles and K{\"o}ttgen, Anna and Lange, Leslie A and Lasky-Su, Jessica and Levy, Daniel and Lin, Xihong and Lin, Keng-Han and Liu, Chunyu and Loos, Ruth J F and Garman, Lori and Gerszten, Robert and Lubitz, Steven A and Lunetta, Kathryn L and Mak, Angel C Y and Manichaikul, Ani and Manning, Alisa K and Mathias, Rasika A and McManus, David D and McGarvey, Stephen T and Meigs, James B and Meyers, Deborah A and Mikulla, Julie L and Minear, Mollie A and Mitchell, Braxton D and Mohanty, Sanghamitra and Montasser, May E and Montgomery, Courtney and Morrison, Alanna C and Murabito, Joanne M and Natale, Andrea and Natarajan, Pradeep and Nelson, Sarah C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pankratz, Nathan and Peloso, Gina M and Peyser, Patricia A and Pleiness, Jacob and Post, Wendy S and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Roden, Dan and Rotter, Jerome I and Ruczinski, Ingo and Sarnowski, Chloe and Schoenherr, Sebastian and Schwartz, David A and Seo, Jeong-Sun and Seshadri, Sudha and Sheehan, Vivien A and Sheu, Wayne H and Shoemaker, M Benjamin and Smith, Nicholas L and Smith, Jennifer A and Sotoodehnia, Nona and Stilp, Adrienne M and Tang, Weihong and Taylor, Kent D and Telen, Marilyn and Thornton, Timothy A and Tracy, Russell P and Van Den Berg, David J and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Vrieze, Scott and Weeks, Daniel E and Weir, Bruce S and Weiss, Scott T and Weng, Lu-Chen and Willer, Cristen J and Zhang, Yingze and Zhao, Xutong and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Boerwinkle, Eric and Gabriel, Stacey and Gibbs, Richard and Rice, Kenneth M and Rich, Stephen S and Silverman, Edwin K and Qasba, Pankaj and Gan, Weiniu and Papanicolaou, George J and Nickerson, Deborah A and Browning, Sharon R and Zody, Michael C and Z{\"o}llner, Sebastian and Wilson, James G and Cupples, L Adrienne and Laurie, Cathy C and Jaquish, Cashell E and Hernandez, Ryan D and O{\textquoteright}Connor, Timothy D and Abecasis, Goncalo R} } @article {8913, title = {Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.}, journal = {Hum Mol Genet}, year = {2021}, month = {2021 Sep 06}, abstract = {

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI{\textquoteright}s Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddab252}, author = {Little, Amarise and Hu, Yao and Sun, Quan and Jain, Deepti and Broome, Jai and Chen, Ming-Huei and Thibord, Florian and McHugh, Caitlin and Surendran, Praveen and Blackwell, Thomas W and Brody, Jennifer A and Bhan, Arunoday and Chami, Nathalie and Vries, Paul S and Ekunwe, Lynette and Heard-Costa, Nancy and Hobbs, Brian D and Manichaikul, Ani and Moon, Jee-Young and Preuss, Michael H and Ryan, Kathleen and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Abecasis, Goncalo R and Almasy, Laura and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Choquet, Helene and Correa, Adolfo and Curran, Joanne E and Faraday, Nauder and Fornage, Myriam and Glahn, David C and Hou, Lifang and Jorgenson, Eric and Kooperberg, Charles and Lewis, Joshua P and Lloyd-Jones, Donald M and Loos, Ruth J F and Min, Nancy and Mitchell, Braxton D and Morrison, Alanna C and Nickerson, Debbie and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Pankratz, Nathan and Psaty, Bruce M and Vasan, Ramachandran S and Rich, Stephen S and Rotter, Jerome I and Smith, Albert V and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Conomos, Matthew P and Laurie, Cecelia A and Mathias, Rasika A and Li, Yun and Auer, Paul L and Thornton, Timothy and Reiner, Alexander P and Johnson, Andrew D and Raffield, Laura M} } @article {8779, title = {Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 05 06}, pages = {874-893}, abstract = {

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3~bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.04.003}, author = {Hu, Yao and Stilp, Adrienne M and McHugh, Caitlin P and Rao, Shuquan and Jain, Deepti and Zheng, Xiuwen and Lane, John and M{\'e}ric de Bellefon, S{\'e}bastian and Raffield, Laura M and Chen, Ming-Huei and Yanek, Lisa R and Wheeler, Marsha and Yao, Yao and Ren, Chunyan and Broome, Jai and Moon, Jee-Young and de Vries, Paul S and Hobbs, Brian D and Sun, Quan and Surendran, Praveen and Brody, Jennifer A and Blackwell, Thomas W and Choquet, Helene and Ryan, Kathleen and Duggirala, Ravindranath and Heard-Costa, Nancy and Wang, Zhe and Chami, Nathalie and Preuss, Michael H and Min, Nancy and Ekunwe, Lynette and Lange, Leslie A and Cushman, Mary and Faraday, Nauder and Curran, Joanne E and Almasy, Laura and Kundu, Kousik and Smith, Albert V and Gabriel, Stacey and Rotter, Jerome I and Fornage, Myriam and Lloyd-Jones, Donald M and Vasan, Ramachandran S and Smith, Nicholas L and North, Kari E and Boerwinkle, Eric and Becker, Lewis C and Lewis, Joshua P and Abecasis, Goncalo R and Hou, Lifang and O{\textquoteright}Connell, Jeffrey R and Morrison, Alanna C and Beaty, Terri H and Kaplan, Robert and Correa, Adolfo and Blangero, John and Jorgenson, Eric and Psaty, Bruce M and Kooperberg, Charles and Walton, Russell T and Kleinstiver, Benjamin P and Tang, Hua and Loos, Ruth J F and Soranzo, Nicole and Butterworth, Adam S and Nickerson, Debbie and Rich, Stephen S and Mitchell, Braxton D and Johnson, Andrew D and Auer, Paul L and Li, Yun and Mathias, Rasika A and Lettre, Guillaume and Pankratz, Nathan and Laurie, Cathy C and Laurie, Cecelia A and Bauer, Daniel E and Conomos, Matthew P and Reiner, Alexander P} } @article {8914, title = {Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 10 07}, pages = {1836-1851}, abstract = {

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

}, keywords = {Asthma, Biomarkers, Dermatitis, Atopic, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Leukocytes, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proteome, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, United Kingdom, United States, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.08.007}, author = {Mikhaylova, Anna V and McHugh, Caitlin P and Polfus, Linda M and Raffield, Laura M and Boorgula, Meher Preethi and Blackwell, Thomas W and Brody, Jennifer A and Broome, Jai and Chami, Nathalie and Chen, Ming-Huei and Conomos, Matthew P and Cox, Corey and Curran, Joanne E and Daya, Michelle and Ekunwe, Lynette and Glahn, David C and Heard-Costa, Nancy and Highland, Heather M and Hobbs, Brian D and Ilboudo, Yann and Jain, Deepti and Lange, Leslie A and Miller-Fleming, Tyne W and Min, Nancy and Moon, Jee-Young and Preuss, Michael H and Rosen, Jonathon and Ryan, Kathleen and Smith, Albert V and Sun, Quan and Surendran, Praveen and de Vries, Paul S and Walter, Klaudia and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Zhong, Xue and Abecasis, Goncalo R and Almasy, Laura and Barnes, Kathleen C and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Chavan, Sameer and Cho, Michael H and Choquet, Helene and Correa, Adolfo and Cox, Nancy and DeMeo, Dawn L and Faraday, Nauder and Fornage, Myriam and Gerszten, Robert E and Hou, Lifang and Johnson, Andrew D and Jorgenson, Eric and Kaplan, Robert and Kooperberg, Charles and Kundu, Kousik and Laurie, Cecelia A and Lettre, Guillaume and Lewis, Joshua P and Li, Bingshan and Li, Yun and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani and Meyers, Deborah A and Mitchell, Braxton D and Morrison, Alanna C and Ngo, Debby and Nickerson, Deborah A and Nongmaithem, Suraj and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Ortega, Victor E and Pankratz, Nathan and Perry, James A and Psaty, Bruce M and Rich, Stephen S and Soranzo, Nicole and Rotter, Jerome I and Silverman, Edwin K and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Thornton, Timothy A and Vasan, Ramachandran S and Zein, Joe and Mathias, Rasika A and Reiner, Alexander P and Auer, Paul L} } @article {9253, title = {A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.}, journal = {Nat Methods}, volume = {19}, year = {2022}, month = {2022 Dec}, pages = {1599-1611}, abstract = {

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

}, keywords = {Genetic Variation, Genome, Genome-Wide Association Study, Humans, Phenotype, Whole Genome Sequencing}, issn = {1548-7105}, doi = {10.1038/s41592-022-01640-x}, author = {Li, Zilin and Li, Xihao and Zhou, Hufeng and Gaynor, Sheila M and Selvaraj, Margaret Sunitha and Arapoglou, Theodore and Quick, Corbin and Liu, Yaowu and Chen, Han and Sun, Ryan and Dey, Rounak and Arnett, Donna K and Auer, Paul L and Bielak, Lawrence F and Bis, Joshua C and Blackwell, Thomas W and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Conomos, Matthew P and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and de Vries, Paul S and Duggirala, Ravindranath and Franceschini, Nora and Freedman, Barry I and G{\"o}ring, Harald H H and Guo, Xiuqing and Kalyani, Rita R and Kooperberg, Charles and Kral, Brian G and Lange, Leslie A and Lin, Bridget M and Manichaikul, Ani and Manning, Alisa K and Martin, Lisa W and Mathias, Rasika A and Meigs, James B and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Rice, Kenneth M and Rich, Stephen S and Smith, Jennifer A and Taylor, Kent D and Taub, Margaret A and Vasan, Ramachandran S and Weeks, Daniel E and Wilson, James G and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Willer, Cristen J and Natarajan, Pradeep and Peloso, Gina M and Lin, Xihong} } @article {9099, title = {Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.}, journal = {Hypertension}, year = {2022}, month = {2022 Jun 02}, pages = {101161HYPERTENSIONAHA12219324}, abstract = {

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5{\texttimes}10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99{\texttimes}10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18{\texttimes}10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28{\texttimes}10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1{\texttimes}10 and <1{\texttimes}10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.122.19324}, author = {Kelly, Tanika N and Sun, Xiao and He, Karen Y and Brown, Michael R and Taliun, Sarah A Gagliano and Hellwege, Jacklyn N and Irvin, Marguerite R and Mi, Xuenan and Brody, Jennifer A and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and de Vries, Paul S and Gao, Yan and Moscati, Arden and Nadkarni, Girish N and Yanek, Lisa R and Elfassy, Tali and Smith, Jennifer A and Chung, Ren-Hua and Beitelshees, Amber L and Patki, Amit and Aslibekyan, Stella and Blobner, Brandon M and Peralta, Juan M and Assimes, Themistocles L and Palmas, Walter R and Liu, Chunyu and Bress, Adam P and Huang, Zhijie and Becker, Lewis C and Hwa, Chii-Min and O{\textquoteright}Connell, Jeffrey R and Carlson, Jenna C and Warren, Helen R and Das, Sayantan and Giri, Ayush and Martin, Lisa W and Craig Johnson, W and Fox, Ervin R and Bottinger, Erwin P and Razavi, Alexander C and Vaidya, Dhananjay and Chuang, Lee-Ming and Chang, Yen-Pei C and Naseri, Take and Jain, Deepti and Kang, Hyun Min and Hung, Adriana M and Srinivasasainagendra, Vinodh and Snively, Beverly M and Gu, Dongfeng and Montasser, May E and Reupena, Muagututi{\textquoteright}a Sefuiva and Heavner, Benjamin D and LeFaive, Jonathon and Hixson, James E and Rice, Kenneth M and Wang, Fei Fei and Nielsen, Jonas B and Huang, Jianfeng and Khan, Alyna T and Zhou, Wei and Nierenberg, Jovia L and Laurie, Cathy C and Armstrong, Nicole D and Shi, Mengyao and Pan, Yang and Stilp, Adrienne M and Emery, Leslie and Wong, Quenna and Hawley, Nicola L and Minster, Ryan L and Curran, Joanne E and Munroe, Patricia B and Weeks, Daniel E and North, Kari E and Tracy, Russell P and Kenny, Eimear E and Shimbo, Daichi and Chakravarti, Aravinda and Rich, Stephen S and Reiner, Alex P and Blangero, John and Redline, Susan and Mitchell, Braxton D and Rao, Dabeeru C and Ida Chen, Yii-Der and Kardia, Sharon L R and Kaplan, Robert C and Mathias, Rasika A and He, Jiang and Psaty, Bruce M and Fornage, Myriam and Loos, Ruth J F and Correa, Adolfo and Boerwinkle, Eric and Rotter, Jerome I and Kooperberg, Charles and Edwards, Todd L and Abecasis, Goncalo R and Zhu, Xiaofeng and Levy, Daniel and Arnett, Donna K and Morrison, Alanna C} } @article {8975, title = {Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.}, journal = {Am J Hum Genet}, volume = {109}, year = {2022}, month = {2022 01 06}, pages = {81-96}, abstract = {

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1\%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

}, keywords = {Alleles, Blood Glucose, Case-Control Studies, Computational Biology, Databases, Genetic, Diabetes Mellitus, Type 2, Exome, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Lipid Metabolism, Lipids, Liver, Molecular Sequence Annotation, Multifactorial Inheritance, Open Reading Frames, Phenotype, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.11.021}, author = {Hindy, George and Dornbos, Peter and Chaffin, Mark D and Liu, Dajiang J and Wang, Minxian and Selvaraj, Margaret Sunitha and Zhang, David and Park, Joseph and Aguilar-Salinas, Carlos A and Antonacci-Fulton, Lucinda and Ardissino, Diego and Arnett, Donna K and Aslibekyan, Stella and Atzmon, Gil and Ballantyne, Christie M and Barajas-Olmos, Francisco and Barzilai, Nir and Becker, Lewis C and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Bown, Matthew J and Brody, Jennifer A and Broome, Jai G and Burtt, Noel P and Cade, Brian E and Centeno-Cruz, Federico and Chan, Edmund and Chang, Yi-Cheng and Chen, Yii-der I and Cheng, Ching-Yu and Choi, Won Jung and Chowdhury, Rajiv and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio J and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Danesh, John and de Vries, Paul S and DeFronzo, Ralph A and Doddapaneni, Harsha and Duggirala, Ravindranath and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Florez, Jose C and Fornage, Myriam and Freedman, Barry I and Fuster, Valentin and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Germer, Soren and Gibbs, Richard A and Gieger, Christian and Glaser, Benjamin and Gonzalez, Clicerio and Gonzalez-Villalpando, Maria Elena and Graff, Mariaelisa and Graham, Sarah E and Grarup, Niels and Groop, Leif C and Guo, Xiuqing and Gupta, Namrata and Han, Sohee and Hanis, Craig L and Hansen, Torben and He, Jiang and Heard-Costa, Nancy L and Hung, Yi-Jen and Hwang, Mi Yeong and Irvin, Marguerite R and Islas-Andrade, Sergio and Jarvik, Gail P and Kang, Hyun Min and Kardia, Sharon L R and Kelly, Tanika and Kenny, Eimear E and Khan, Alyna T and Kim, Bong-Jo and Kim, Ryan W and Kim, Young Jin and Koistinen, Heikki A and Kooperberg, Charles and Kuusisto, Johanna and Kwak, Soo Heon and Laakso, Markku and Lange, Leslie A and Lee, Jiwon and Lee, Juyoung and Lee, Seonwook and Lehman, Donna M and Lemaitre, Rozenn N and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lubitz, Steven A and Lyssenko, Valeriya and Ma, Ronald C W and Martin, Lisa Warsinger and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Mathias, Rasika A and McGarvey, Stephen T and McPherson, Ruth and Meigs, James B and Meitinger, Thomas and Melander, Olle and Mendoza-Caamal, Elvia and Metcalf, Ginger A and Mi, Xuenan and Mohlke, Karen L and Montasser, May E and Moon, Jee-Young and Moreno-Macias, Hortensia and Morrison, Alanna C and Muzny, Donna M and Nelson, Sarah C and Nilsson, Peter M and O{\textquoteright}Connell, Jeffrey R and Orho-Melander, Marju and Orozco, Lorena and Palmer, Colin N A and Palmer, Nicholette D and Park, Cheol Joo and Park, Kyong Soo and Pedersen, Oluf and Peralta, Juan M and Peyser, Patricia A and Post, Wendy S and Preuss, Michael and Psaty, Bruce M and Qi, Qibin and Rao, D C and Redline, Susan and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Samani, Nilesh and Schunkert, Heribert and Schurmann, Claudia and Seo, Daekwan and Seo, Jeong-Sun and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Stilp, Adrienne M and Tai, E Shyong and Tam, Claudia H T and Taylor, Kent D and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tsai, Michael Y and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and van Dam, Rob M and Vasan, Ramachandran S and Viaud Martinez, Karine A and Wang, Fei Fei and Wang, Xuzhi and Watkins, Hugh and Weeks, Daniel E and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Yanek, Lisa R and Kathiresan, Sekar and Rader, Daniel J and Rotter, Jerome I and Boehnke, Michael and McCarthy, Mark I and Willer, Cristen J and Natarajan, Pradeep and Flannick, Jason A and Khera, Amit V and Peloso, Gina M} } @article {9158, title = {Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 07 28}, pages = {756}, abstract = {

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

}, keywords = {Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States}, issn = {2399-3642}, doi = {10.1038/s42003-022-03702-4}, author = {DiCorpo, Daniel and Gaynor, Sheila M and Russell, Emily M and Westerman, Kenneth E and Raffield, Laura M and Majarian, Timothy D and Wu, Peitao and Sarnowski, Chloe and Highland, Heather M and Jackson, Anne and Hasbani, Natalie R and de Vries, Paul S and Brody, Jennifer A and Hidalgo, Bertha and Guo, Xiuqing and Perry, James A and O{\textquoteright}Connell, Jeffrey R and Lent, Samantha and Montasser, May E and Cade, Brian E and Jain, Deepti and Wang, Heming and D{\textquoteright}Oliveira Albanus, Ricardo and Varshney, Arushi and Yanek, Lisa R and Lange, Leslie and Palmer, Nicholette D and Almeida, Marcio and Peralta, Juan M and Aslibekyan, Stella and Baldridge, Abigail S and Bertoni, Alain G and Bielak, Lawrence F and Chen, Chung-Shiuan and Chen, Yii-Der Ida and Choi, Won Jung and Goodarzi, Mark O and Floyd, James S and Irvin, Marguerite R and Kalyani, Rita R and Kelly, Tanika N and Lee, Seonwook and Liu, Ching-Ti and Loesch, Douglas and Manson, JoAnn E and Minster, Ryan L and Naseri, Take and Pankow, James S and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Selvin, Elizabeth and Smith, Jennifer A and Weeks, Daniel E and Xu, Huichun and Yao, Jie and Zhao, Wei and Parker, Stephen and Alonso, Alvaro and Arnett, Donna K and Blangero, John and Boerwinkle, Eric and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Duggirala, Ravindranath and He, Jiang and Heckbert, Susan R and Kardia, Sharon L R and Kim, Ryan W and Kooperberg, Charles and Liu, Simin and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Morrison, Alanna C and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Shuldiner, Alan R and Taylor, Kent D and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Florez, Jose C and Wilson, James G and Sladek, Robert and Rich, Stephen S and Rotter, Jerome I and Lin, Xihong and Dupuis, Jos{\'e}e and Meigs, James B and Wessel, Jennifer and Manning, Alisa K} } @article {9261, title = {Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Dec 08}, pages = {7592}, abstract = {

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

}, keywords = {Blood Cells, Genome-Wide Association Study, Humans, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-022-35354-7}, author = {Wheeler, Marsha M and Stilp, Adrienne M and Rao, Shuquan and Halldorsson, Bjarni V and Beyter, Doruk and Wen, Jia and Mihkaylova, Anna V and McHugh, Caitlin P and Lane, John and Jiang, Min-Zhi and Raffield, Laura M and Jun, Goo and Sedlazeck, Fritz J and Metcalf, Ginger and Yao, Yao and Bis, Joshua B and Chami, Nathalie and de Vries, Paul S and Desai, Pinkal and Floyd, James S and Gao, Yan and Kammers, Kai and Kim, Wonji and Moon, Jee-Young and Ratan, Aakrosh and Yanek, Lisa R and Almasy, Laura and Becker, Lewis C and Blangero, John and Cho, Michael H and Curran, Joanne E and Fornage, Myriam and Kaplan, Robert C and Lewis, Joshua P and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Preuss, Michael and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Tang, Hua and Tracy, Russell P and Boerwinkle, Eric and Abecasis, Goncalo R and Blackwell, Thomas W and Smith, Albert V and Johnson, Andrew D and Mathias, Rasika A and Nickerson, Deborah A and Conomos, Matthew P and Li, Yun and {\TH}orsteinsdottir, Unnur and Magn{\'u}sson, Magn{\'u}s K and Stefansson, Kari and Pankratz, Nathan D and Bauer, Daniel E and Auer, Paul L and Reiner, Alex P} } @article {9387, title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.}, journal = {Nature}, volume = {616}, year = {2023}, month = {2023 Apr}, pages = {755-763}, abstract = {

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but~this effect was not seen in~clones with~driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental~knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

}, keywords = {Alleles, Animals, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mutation, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/s41586-023-05806-1}, author = {Weinstock, Joshua S and Gopakumar, Jayakrishnan and Burugula, Bala Bharathi and Uddin, Md Mesbah and Jahn, Nikolaus and Belk, Julia A and Bouzid, Hind and Daniel, Bence and Miao, Zhuang and Ly, Nghi and Mack, Taralynn M and Luna, Sofia E and Prothro, Katherine P and Mitchell, Shaneice R and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Sinner, Moritz F and von Falkenhausen, Aenne S and K{\"a}{\"a}b, Stefan and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Hou, Lifang and Lloyd-Jones, Donald M and Redline, Susan and Cade, Brian E and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and DeMeo, Dawn L and Vasan, Ramachandran S and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon L R and Peyser, Patricia A and He, Jiang and Rienstra, Michiel and van der Harst, Pim and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Cutler, Michael J and Knight, Stacey and Muhlestein, J Brent and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Smith, J Gustav and Melander, Olle and Nilsson, Peter M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and McGarvey, Stephen and Williams, L Keoki and Xiao, Shujie and Yang, Mao and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Marcus, Gregory M and Kane, John P and Pullinger, Clive R and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan M and Albert, Christine and Kooperberg, Charles and Zhou, Ying and Manson, JoAnn E and Desai, Pinkal and Johnson, Andrew D and Mathias, Rasika A and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Satpathy, Ansuman T and Natarajan, Pradeep and Kitzman, Jacob O and Whitsel, Eric A and Reiner, Alexander P and Bick, Alexander G and Jaiswal, Siddhartha} } @article {9323, title = {Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.}, journal = {Neurology}, year = {2023}, month = {2023 Mar 16}, abstract = {

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer{\textquoteright}s disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within {\textpm}5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. >=60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57\% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95\% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000207157}, author = {Zhang, Yuankai and Liu, Xue and Wiggins, Kerri L and Kurniansyah, Nuzulul and Guo, Xiuqing and Rodrigue, Amanda L and Zhao, Wei and Yanek, Lisa R and Ratliff, Scott M and Pitsillides, Achilleas and Aguirre Pati{\~n}o, Juan Sebastian and Sofer, Tamar and Arking, Dan E and Austin, Thomas R and Beiser, Alexa S and Blangero, John and Boerwinkle, Eric and Bressler, Jan and Curran, Joanne E and Hou, Lifang and Hughes, Timothy M and Kardia, Sharon L and Launer, Lenore and Levy, Daniel and Mosley, Tom H and Nasrallah, Ilya M and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Tarraf, Wassim and Gonz{\'a}lez, Kevin A and Ramachandran, Vasan and Yaffe, Kristine and Nyquist, Paul A and Psaty, Bruce M and DeCarli, Charles S and Smith, Jennifer A and Glahn, David C and Gonz{\'a}lez, Hector M and Bis, Joshua C and Fornage, Myriam and Heckbert, Susan R and Fitzpatrick, Annette L and Liu, Chunyu and Satizabal, Claudia L} } @article {9479, title = {Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 16}, abstract = {

BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.

METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.

RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14\%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95\%CI: 0.39-0.96; OR : 0.64 95\%CI: 0.34-1.19; OR : 0.64 95\%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.

CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

}, doi = {10.1101/2023.08.14.23294063}, author = {Georgakis, Marios K and Malik, Rainer and Hasbani, Natalie R and Shakt, Gabrielle and Morrison, Alanna C and Tsao, Noah L and Judy, Renae and Mitchell, Braxton D and Xu, Huichun and Montasser, May E and Do, Ron and Kenny, Eimear E and Loos, Ruth J F and Terry, James G and Carr, John Jeffrey and Bis, Joshua C and Psaty, Bruce M and Longstreth, W T and Young, Kendra A and Lutz, Sharon M and Cho, Michael H and Broome, Jai and Khan, Alyna T and Wang, Fei Fei and Heard-Costa, Nancy and Seshadri, Sudha and Vasan, Ramachandran S and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Yanek, Lisa R and Kral, Brian G and Becker, Lewis C and Peyser, Patricia A and Bielak, Lawrence F and Ammous, Farah and Carson, April P and Hall, Michael E and Raffield, Laura M and Rich, Stephen S and Post, Wendy S and Tracy, Russel P and Taylor, Kent D and Guo, Xiuqing and Mahaney, Michael C and Curran, Joanne E and Blangero, John and Clarke, Shoa L and Haessler, Jeffrey W and Hu, Yao and Assimes, Themistocles L and Kooperberg, Charles and Damrauer, Scott M and Rotter, Jerome I and de Vries, Paul S and Dichgans, Martin} } @article {9419, title = {The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.}, journal = {Sci Adv}, volume = {9}, year = {2023}, month = {2023 Apr 28}, pages = {eabm4945}, abstract = {

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

}, keywords = {Germ-Line Mutation, Hematopoiesis, Humans, Middle Aged, Mutation, Mutation, Missense, Phenotype}, issn = {2375-2548}, doi = {10.1126/sciadv.abm4945}, author = {Weinstock, Joshua S and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Redline, Susan and Cade, Brian E and Gilliland, Frank D and Chen, Zhanghua and Gauderman, W James and Kumar, Rajesh and Grammer, Leslie and Schleimer, Robert P and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Weiss, Scott T and Lasky-Su, Jessica and DeMeo, Dawn L and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and Vasan, Ramachandran S and Johnson, Andrew D and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon and He, Jiang and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Manichaikul, Ani W and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and Gui, Hongsheng and Xiao, Shujie and Williams, L Keoki and Meyers, Deborah A and Li, Xingnan and Ortega, Victor and McGarvey, Stephen and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan and Albert, Christine and Kooperberg, Charles and Desai, Pinkal and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Mathias, Rasika and Natarajan, Pradeep and Jaiswal, Siddhartha and Reiner, Alexander P and Bick, Alexander G} } @article {9412, title = {Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Feb}, pages = {291-300}, abstract = {

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55\% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

}, keywords = {Biology, Drug Repositioning, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Tobacco Use, Transcriptome}, issn = {1546-1718}, doi = {10.1038/s41588-022-01282-x}, author = {Chen, Fang and Wang, Xingyan and Jang, Seon-Kyeong and Quach, Bryan C and Weissenkampen, J Dylan and Khunsriraksakul, Chachrit and Yang, Lina and Sauteraud, Renan and Albert, Christine M and Allred, Nicholette D D and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Barr, R Graham and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boorgula, Meher Preethi and Chasman, Daniel I and Chavan, Sameer and Chen, Yii-der I and Chuang, Lee-Ming and Correa, Adolfo and Curran, Joanne E and David, Sean P and Fuentes, Lisa de Las and Deka, Ranjan and Duggirala, Ravindranath and Faul, Jessica D and Garrett, Melanie E and Gharib, Sina A and Guo, Xiuqing and Hall, Michael E and Hawley, Nicola L and He, Jiang and Hobbs, Brian D and Hokanson, John E and Hsiung, Chao A and Hwang, Shih-Jen and Hyde, Thomas M and Irvin, Marguerite R and Jaffe, Andrew E and Johnson, Eric O and Kaplan, Robert and Kardia, Sharon L R and Kaufman, Joel D and Kelly, Tanika N and Kleinman, Joel E and Kooperberg, Charles and Lee, I-Te and Levy, Daniel and Lutz, Sharon M and Manichaikul, Ani W and Martin, Lisa W and Marx, Olivia and McGarvey, Stephen T and Minster, Ryan L and Moll, Matthew and Moussa, Karine A and Naseri, Take and North, Kari E and Oelsner, Elizabeth C and Peralta, Juan M and Peyser, Patricia A and Psaty, Bruce M and Rafaels, Nicholas and Raffield, Laura M and Reupena, Muagututi{\textquoteright}a Sefuiva and Rich, Stephen S and Rotter, Jerome I and Schwartz, David A and Shadyab, Aladdin H and Sheu, Wayne H-H and Sims, Mario and Smith, Jennifer A and Sun, Xiao and Taylor, Kent D and Telen, Marilyn J and Watson, Harold and Weeks, Daniel E and Weir, David R and Yanek, Lisa R and Young, Kendra A and Young, Kristin L and Zhao, Wei and Hancock, Dana B and Jiang, Bibo and Vrieze, Scott and Liu, Dajiang J} } @article {9239, title = {Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Jan}, pages = {154-164}, abstract = {

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

}, keywords = {Exome Sequencing, Genome-Wide Association Study, Lipids, Phenotype, Whole Genome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-022-01225-6}, author = {Li, Xihao and Quick, Corbin and Zhou, Hufeng and Gaynor, Sheila M and Liu, Yaowu and Chen, Han and Selvaraj, Margaret Sunitha and Sun, Ryan and Dey, Rounak and Arnett, Donna K and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and de Vries, Paul S and Duggirala, Ravindranath and Freedman, Barry I and G{\"o}ring, Harald H H and Guo, Xiuqing and Haessler, Jeffrey and Kalyani, Rita R and Kooperberg, Charles and Kral, Brian G and Lange, Leslie A and Manichaikul, Ani and Martin, Lisa W and McGarvey, Stephen T and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Rice, Kenneth M and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Vasan, Ramachandran S and Willer, Cristen J and Wilson, James G and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Natarajan, Pradeep and Peloso, Gina M and Li, Zilin and Lin, Xihong} } @article {9418, title = {Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 29}, abstract = {

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a {\textpm}500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73\%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56\%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

}, doi = {10.1101/2023.06.28.23291966}, author = {Wang, Yuxuan and Selvaraj, Margaret Sunitha and Li, Xihao and Li, Zilin and Holdcraft, Jacob A and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Cade, Brian E and Carlson, Jenna C and Carson, April P and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Dutcher, Susan K and Ellinor, Patrick T and Floyd, James S and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and Guo, Xiuqing and He, Jiang and Heard-Costa, Nancy and Hildalgo, Bertha and Hou, Lifang and Irvin, Marguerite R and Joehanes, Roby and Kaplan, Robert C and Kardia, Sharon Lr and Kelly, Tanika N and Kim, Ryan and Kooperberg, Charles and Kral, Brian G and Levy, Daniel and Li, Changwei and Liu, Chunyu and Lloyd-Jone, Don and Loos, Ruth Jf and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Murabito, Joanne M and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Rao, Dabeeru C and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Ruepena, Muagututi{\textquoteright}a Sefuiva and Sheu, Wayne H-H and Smith, Jennifer A and Smith, Albert and Tiwari, Hemant K and Tsai, Michael Y and Viaud-Martinez, Karine A and Wang, Zhe and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Lin, Xihong and Natarajan, Pradeep and Peloso, Gina M} } @article {9543, title = {A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {bioRxiv}, year = {2023}, month = {2023 Nov 02}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

}, doi = {10.1101/2023.10.30.564764}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant and Vasan, Ramachandran S and Wang, Zhe and Yanek, Lisa R and Yu, Bing and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} } @article {9537, title = {Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.}, journal = {Circ Genom Precis Med}, year = {2023}, month = {2023 Nov 28}, pages = {e004176}, abstract = {

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

RESULTS: Using a Bonferroni-corrected significance threshold of <1.6{\texttimes}10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.123.004176}, author = {Hasbani, Natalie R and Westerman, Kenneth E and Heon Kwak, Soo and Chen, Han and Li, Xihao and DiCorpo, Daniel and Wessel, Jennifer and Bis, Joshua C and Sarnowski, Chloe and Wu, Peitao and Bielak, Lawrence F and Guo, Xiuqing and Heard-Costa, Nancy and Kinney, Gregory and Mahaney, Michael C and Montasser, May E and Palmer, Nicholette D and Raffield, Laura M and Terry, James G and Yanek, Lisa R and Bon, Jessica and Bowden, Donald W and Brody, Jennifer A and Duggirala, Ravindranath and Jacobs, David R and Kalyani, Rita R and Lange, Leslie A and Mitchell, Braxton D and Smith, Jennifer A and Taylor, Kent D and Carson, April and Curran, Joanne E and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Gibbs, Richard A and Gupta, Namrata and Kardia, Sharon L R and Kral, Brian G and Momin, Zeineen and Newman, Anne B and Post, Wendy S and Viaud-Martinez, Karine A and Young, Kendra A and Becker, Lewis C and Bertoni, Alain and Blangero, John and Carr, John J and Pratte, Katherine and Psaty, Bruce M and Rich, Stephen S and Wu, Joseph C and Malhotra, Rajeev and Peyser, Patricia A and Morrison, Alanna C and Vasan, Ramachandran S and Lin, Xihong and Rotter, Jerome I and Meigs, James B and Manning, Alisa K and de Vries, Paul S} } @article {9449, title = {Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 12}, abstract = {

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10\% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

}, doi = {10.1101/2023.06.07.23291095}, author = {Huffman, Jennifer E and Nicolas, Jayna and Hahn, Julie and Heath, Adam S and Raffield, Laura M and Yanek, Lisa R and Brody, Jennifer A and Thibord, Florian and Almasy, Laura and Bartz, Traci M and Bielak, Lawrence F and Bowler, Russell P and Carrasquilla, Germ{\'a}n D and Chasman, Daniel I and Chen, Ming-Huei and Emmert, David B and Ghanbari, Mohsen and Haessle, Jeffery and Hottenga, Jouke-Jan and Kleber, Marcus E and Le, Ngoc-Quynh and Lee, Jiwon and Lewis, Joshua P and Li-Gao, Ruifang and Luan, Jian{\textquoteright}an and Malmberg, Anni and Mangino, Massimo and Marioni, Riccardo E and Martinez-Perez, Angel and Pankratz, Nathan and Polasek, Ozren and Richmond, Anne and Rodriguez, Benjamin At and Rotter, Jerome I and Steri, Maristella and Suchon, Pierre and Trompet, Stella and Weiss, Stefan and Zare, Marjan and Auer, Paul and Cho, Michael H and Christofidou, Paraskevi and Davies, Gail and de Geus, Eco and Deleuze, Jean-Francois and Delgado, Graciela E and Ekunwe, Lynette and Faraday, Nauder and G{\"o}gele, Martin and Greinacher, Andreas and He, Gao and Howard, Tom and Joshi, Peter K and Kilpel{\"a}inen, Tuomas O and Lahti, Jari and Linneberg, Allan and Naitza, Silvia and Noordam, Raymond and Pa{\"u}ls-Verg{\'e}s, Ferran and Rich, Stephen S and Rosendaal, Frits R and Rudan, Igor and Ryan, Kathleen A and Souto, Juan Carlos and van Rooij, Frank Ja and Wang, Heming and Zhao, Wei and Becker, Lewis C and Beswick, Andrew and Brown, Michael R and Cade, Brian E and Campbell, Harry and Cho, Kelly and Crapo, James D and Curran, Joanne E and de Maat, Moniek Pm and Doyle, Margaret and Elliott, Paul and Floyd, James S and Fuchsberger, Christian and Grarup, Niels and Guo, Xiuqing and Harris, Sarah E and Hou, Lifang and Kolcic, Ivana and Kooperberg, Charles and Menni, Cristina and Nauck, Matthias and O{\textquoteright}Connell, Jeffrey R and Orr{\`u}, Valeria and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Smith, Jennifer A and Soria, Jos{\'e} Manuel and Stott, David J and van Hylckama Vlieg, Astrid and Watkins, Hugh and Willemsen, Gonneke and Wilson, Peter and Ben-Shlomo, Yoav and Blangero, John and Boomsma, Dorret and Cox, Simon R and Dehghan, Abbas and Eriksson, Johan G and Fiorillo, Edoardo and Fornage, Myriam and Hansen, Torben and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon Lr and Lange, Leslie A and M{\"a}rz, Winfried and Mathias, Rasika A and Mitchell, Braxton D and Mook-Kanamori, Dennis O and Morange, Pierre-Emmanuel and Pedersen, Oluf and Pramstaller, Peter P and Redline, Susan and Reiner, Alexander and Ridker, Paul M and Silverman, Edwin K and Spector, Tim D and V{\"o}lker, Uwe and Wareham, Nick and Wilson, James F and Yao, Jie and Tr{\'e}gou{\"e}t, David-Alexandre and Johnson, Andrew D and Wolberg, Alisa S and de Vries, Paul S and Sabater-Lleal, Maria and Morrison, Alanna C and Smith, Nicholas L} } @article {9484, title = {WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 22}, abstract = {

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51\% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 {\texttimes} 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

}, doi = {10.1101/2023.08.21.23293271}, author = {Zhang, Xinruo and Brody, Jennifer A and Graff, Mariaelisa and Highland, Heather M and Chami, Nathalie and Xu, Hanfei and Wang, Zhe and Ferrier, Kendra and Chittoor, Geetha and Josyula, Navya S and Li, Xihao and Li, Zilin and Allison, Matthew A and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Boorgula, Meher Preethi and Bowden, Donald W and Broome, Jai G and Buth, Erin J and Carlson, Christopher S and Chang, Kyong-Mi and Chavan, Sameer and Chiu, Yen-Feng and Chuang, Lee-Ming and Conomos, Matthew P and DeMeo, Dawn L and Du, Margaret and Duggirala, Ravindranath and Eng, Celeste and Fohner, Alison E and Freedman, Barry I and Garrett, Melanie E and Guo, Xiuqing and Haiman, Chris and Heavner, Benjamin D and Hidalgo, Bertha and Hixson, James E and Ho, Yuk-Lam and Hobbs, Brian D and Hu, Donglei and Hui, Qin and Hwu, Chii-Min and Jackson, Rebecca D and Jain, Deepti and Kalyani, Rita R and Kardia, Sharon L R and Kelly, Tanika N and Lange, Ethan M and LeNoir, Michael and Li, Changwei and Marchand, Loic Le and McDonald, Merry-Lynn N and McHugh, Caitlin P and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donnell, Christopher J and Palmer, Nicholette D and Pankow, James S and Perry, James A and Peters, Ulrike and Preuss, Michael H and Rao, D C and Regan, Elizabeth A and Reupena, Sefuiva M and Roden, Dan M and Rodriguez-Santana, Jose and Sitlani, Colleen M and Smith, Jennifer A and Tiwari, Hemant K and Vasan, Ramachandran S and Wang, Zeyuan and Weeks, Daniel E and Wessel, Jennifer and Wiggins, Kerri L and Wilkens, Lynne R and Wilson, Peter W F and Yanek, Lisa R and Yoneda, Zachary T and Zhao, Wei and Z{\"o}llner, Sebastian and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Blangero, John and Boerwinkle, Eric and Burchard, Esteban G and Carson, April P and Chasman, Daniel I and Chen, Yii-Der Ida and Curran, Joanne E and Fornage, Myriam and Gordeuk, Victor R and He, Jiang and Heckbert, Susan R and Hou, Lifang and Irvin, Marguerite R and Kooperberg, Charles and Minster, Ryan L and Mitchell, Braxton D and Nouraie, Mehdi and Psaty, Bruce M and Raffield, Laura M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Shoemaker, M Benjamin and Smith, Nicholas L and Taylor, Kent D and Telen, Marilyn J and Weiss, Scott T and Zhang, Yingze and Costa, Nancy Heard- and Sun, Yan V and Lin, Xihong and Cupples, L Adrienne and Lange, Leslie A and Liu, Ching-Ti and Loos, Ruth J F and North, Kari E and Justice, Anne E} } @article {9707, title = {Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.}, journal = {Nat Cardiovasc Res}, volume = {2}, year = {2023}, month = {2023 Dec}, pages = {1159-1172}, abstract = {

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( and ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of and in human vascular smooth muscle cells (VSMCs) demonstrate that is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near with reduced CAC is likely explained by reduced expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.

}, issn = {2731-0590}, doi = {10.1038/s44161-023-00375-y}, author = {de Vries, Paul S and Conomos, Matthew P and Singh, Kuldeep and Nicholson, Christopher J and Jain, Deepti and Hasbani, Natalie R and Jiang, Wanlin and Lee, Sujin and Lino Cardenas, Christian L and Lutz, Sharon M and Wong, Doris and Guo, Xiuqing and Yao, Jie and Young, Erica P and Tcheandjieu, Catherine and Hilliard, Austin T and Bis, Joshua C and Bielak, Lawrence F and Brown, Michael R and Musharoff, Shaila and Clarke, Shoa L and Terry, James G and Palmer, Nicholette D and Yanek, Lisa R and Xu, Huichun and Heard-Costa, Nancy and Wessel, Jennifer and Selvaraj, Margaret Sunitha and Li, Rebecca H and Sun, Xiao and Turner, Adam W and Stilp, Adrienne M and Khan, Alyna and Newman, Anne B and Rasheed, Asif and Freedman, Barry I and Kral, Brian G and McHugh, Caitlin P and Hodonsky, Chani and Saleheen, Danish and Herrington, David M and Jacobs, David R and Nickerson, Deborah A and Boerwinkle, Eric and Wang, Fei Fei and Heiss, Gerardo and Jun, Goo and Kinney, Greg L and Sigurslid, Haakon H and Doddapaneni, Harshavardhan and Hall, Ira M and Bensenor, Isabela M and Broome, Jai and Crapo, James D and Wilson, James G and Smith, Jennifer A and Blangero, John and Vargas, Jose D and Mosquera, Jose Verdezoto and Smith, Joshua D and Viaud-Martinez, Karine A and Ryan, Kathleen A and Young, Kendra A and Taylor, Kent D and Lange, Leslie A and Emery, Leslie S and Bittencourt, Marcio S and Budoff, Matthew J and Montasser, May E and Yu, Miao and Mahaney, Michael C and Mahamdeh, Mohammed S and Fornage, Myriam and Franceschini, Nora and Lotufo, Paulo A and Natarajan, Pradeep and Wong, Quenna and Mathias, Rasika A and Gibbs, Richard A and Do, Ron and Mehran, Roxana and Tracy, Russell P and Kim, Ryan W and Nelson, Sarah C and Damrauer, Scott M and Kardia, Sharon L R and Rich, Stephen S and Fuster, Valentin and Napolioni, Valerio and Zhao, Wei and Tian, Wenjie and Yin, Xianyong and Min, Yuan-I and Manning, Alisa K and Peloso, Gina and Kelly, Tanika N and O{\textquoteright}Donnell, Christopher J and Morrison, Alanna C and Curran, Joanne E and Zapol, Warren M and Bowden, Donald W and Becker, Lewis C and Correa, Adolfo and Mitchell, Braxton D and Psaty, Bruce M and Carr, John Jeffrey and Pereira, Alexandre C and Assimes, Themistocles L and Stitziel, Nathan O and Hokanson, John E and Laurie, Cecelia A and Rotter, Jerome I and Vasan, Ramachandran S and Post, Wendy S and Peyser, Patricia A and Miller, Clint L and Malhotra, Rajeev} } @article {9898, title = {Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.}, journal = {Genome Med}, volume = {17}, year = {2025}, month = {2025 Mar 21}, pages = {27}, abstract = {

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595).

RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15\% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95\% confidence interval [CI]: 0.54-0.81, p = 6.1 {\texttimes} 10) and coronary artery disease (OR: 0.74, 95\%CI: 0.63-0.87, p = 2.9 {\texttimes} 10) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.

CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

}, keywords = {Aged, Cardiovascular Diseases, Chemokine CCL2, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Monocytes, Receptors, CCR2}, issn = {1756-994X}, doi = {10.1186/s13073-025-01456-2}, author = {Georgakis, Marios K and Malik, Rainer and Bounkari, Omar El and Hasbani, Natalie R and Li, Jiang and Huffman, Jennifer E and Shakt, Gabrielle and Tack, Reinier W P and Kimball, Tamara N and Asare, Yaw and Morrison, Alanna C and Tsao, Noah L and Judy, Renae and Mitchell, Braxton D and Xu, Huichun and Montasser, May E and Do, Ron and Kenny, Eimear E and Loos, Ruth J F and Terry, James G and Carr, John Jeffrey and Bis, Joshua C and Psaty, Bruce M and Longstreth, W T and Young, Kendra A and Lutz, Sharon M and Cho, Michael H and Broome, Jai and Khan, Alyna T and Wang, Fei Fei and Heard-Costa, Nancy and Seshadri, Sudha and Vasan, Ramachandran S and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Yanek, Lisa R and Kral, Brian G and Becker, Lewis C and Peyser, Patricia A and Bielak, Lawrence F and Ammous, Farah and Carson, April P and Hall, Michael E and Raffield, Laura M and Rich, Stephen S and Post, Wendy S and Tracy, Russel P and Taylor, Kent D and Guo, Xiuqing and Mahaney, Michael C and Curran, Joanne E and Blangero, John and Clarke, Shoa L and Haessler, Jeffrey W and Hu, Yao and Assimes, Themistocles L and Kooperberg, Charles and Bernhagen, J{\"u}rgen and Anderson, Christopher D and Damrauer, Scott M and Zand, Ramin and Rotter, Jerome I and de Vries, Paul S and Dichgans, Martin} } @article {9899, title = {A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {Nat Comput Sci}, volume = {5}, year = {2025}, month = {2025 Feb}, pages = {125-143}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.

}, keywords = {Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Lipids, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Whole Genome Sequencing}, issn = {2662-8457}, doi = {10.1038/s43588-024-00764-8}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Jiang, Min-Zhi and DiCorpo, Daniel and Gaynor, Sheila M and Dey, Rounak and Arnett, Donna K and Benjamin, Emelia J and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika N and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Li, Yun and Lin, Honghuang and Liu, Ching-Ti and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and North, Kari E and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant K and Vasan, Ramachandran S and Viali, Satupa{\textquoteright}itea and Wang, Zhe and Wessel, Jennifer and Yanek, Lisa R and Yu, Bing and Dupuis, Jos{\'e}e and Meigs, James B and Auer, Paul L and Raffield, Laura M and Manning, Alisa K and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} } @article {9987, title = {Whole genome sequence association analysis of brain structural volume measures in the NHLBI TOPMed Program highlights novel loci in diverse participants.}, journal = {medRxiv}, year = {2025}, month = {2025 Jun 13}, abstract = {

Brain structural volumes are highly heritable and are linked to multiple neuropsychological outcomes, including Alzheimer{\textquoteright}s disease (AD). Genome-wide association studies have successfully identified genetic variants associated with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), and lateral ventricular volume (LVV). However, these studies mostly focused on common genetic variants with minor allele frequencies (MAF) > 1\%, and individuals included in most of these studies were of predominantly European ancestry. Here, we performed whole-genome sequence (WGS) association studies of MRI brain volumes in 7,674 individuals of diverse race and ethnicity from the Trans-Omics for Precision Medicine (TOPMed) program. We identified novel genetic loci on chromosomes 13 and 16 near and associated with HV and TBV, respectively (lead variants rs115674829, -value = 1.7{\texttimes}10 in pooled analysis and rs150440001, -value = 6.6{\texttimes}10 in black participants). Both lead variant minor A alleles are rarer in white participants (MAF = 0.14\% and 0.03\%) and in Hispanic participants (MAF = 1.5\% and 0.17\%) but more common in black participants (MAF = 13\% and 1.5\%). Rare variant aggregated analyses identified a gene encoding a kinase involved in neuroinflammation and promising target for AD treatment, suggestively associated with LVV (-value=5{\texttimes}10). This study provides new insights into the genetic correlates of brain structural volumes and illustrates the importance of leveraging WGS data and cohorts of diverse race and ethnicity to better characterize the genetic architecture of complex polygenic traits.

}, doi = {10.1101/2025.06.11.25329426}, author = {Shade, Lincoln Mp and Sharifitabar, Mohsen and Beiser, Alexa and Satizabal, Claudia L and Mosley, Thomas H and Curran, Joanne E and Bressler, Jan and Heckbert, Susan R and Hughes, Timothy M and Austin, Thomas R and Nasrallah, Ilya M and Launer, Lenore J and Yanek, Lisa R and Bis, Joshua C and Doddapaneni, Harsha and Gibbs, Richard A and Gabriel, Stacey and Gupta, Namrata and Viaud-Martinez, Karine A and Smith, Albert V and Opsasnick, Lauren A and Ammous, Farrah and Smith, Jennifer A and Arnett, Donna K and Kardia, Sharon L R and Psaty, Bruce M and Longstreth, W T and Mathias, Rasika A and Nyquist, Paul and Rich, Stephen S and Rotter, Jerome I and Boerwinkle, Eric and DeCarli, Charles S and Glahn, David C and Blangero, John and Fornage, Myriam and Fardo, David W and Seshadri, Sudha and Sarnowski, Chloe} } @article {9942, title = {Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.}, journal = {Nat Commun}, volume = {16}, year = {2025}, month = {2025 Apr 11}, pages = {3470}, abstract = {

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51\% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 {\texttimes} 10), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

}, keywords = {Adult, African People, Alleles, Body Mass Index, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Population Groups, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-025-58420-2}, author = {Zhang, Xinruo and Brody, Jennifer A and Graff, Mariaelisa and Highland, Heather M and Chami, Nathalie and Xu, Hanfei and Wang, Zhe and Ferrier, Kendra R and Chittoor, Geetha and Josyula, Navya Shilpa and Meyer, Mariah and Gupta, Shreyash and Li, Xihao and Li, Zilin and Allison, Matthew A and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Boorgula, Meher Preethi and Bowden, Donald W and Broome, Jai G and Buth, Erin J and Carlson, Christopher S and Chang, Kyong-Mi and Chavan, Sameer and Chiu, Yen-Feng and Chuang, Lee-Ming and Conomos, Matthew P and DeMeo, Dawn L and Du, Mengmeng and Duggirala, Ravindranath and Eng, Celeste and Fohner, Alison E and Freedman, Barry I and Garrett, Melanie E and Guo, Xiuqing and Haiman, Chris and Heavner, Benjamin D and Hidalgo, Bertha and Hixson, James E and Ho, Yuk-Lam and Hobbs, Brian D and Hu, Donglei and Hui, Qin and Hwu, Chii-Min and Jackson, Rebecca D and Jain, Deepti and Kalyani, Rita R and Kardia, Sharon L R and Kelly, Tanika N and Lange, Ethan M and LeNoir, Michael and Li, Changwei and Le Marchand, Lo{\"\i}c and McDonald, Merry-Lynn N and McHugh, Caitlin P and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donnell, Christopher J and Palmer, Nicholette D and Pankow, James S and Perry, James A and Peters, Ulrike and Preuss, Michael H and Rao, D C and Regan, Elizabeth A and Reupena, Sefuiva M and Roden, Dan M and Rodriguez-Santana, Jose and Sitlani, Colleen M and Smith, Jennifer A and Tiwari, Hemant K and Vasan, Ramachandran S and Wang, Zeyuan and Weeks, Daniel E and Wessel, Jennifer and Wiggins, Kerri L and Wilkens, Lynne R and Wilson, Peter W F and Yanek, Lisa R and Yoneda, Zachary T and Zhao, Wei and Z{\"o}llner, Sebastian and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Blangero, John and Boerwinkle, Eric and Burchard, Esteban G and Carson, April P and Chasman, Daniel I and Ida Chen, Yii-Der and Curran, Joanne E and Fornage, Myriam and Gordeuk, Victor R and He, Jiang and Heckbert, Susan R and Hou, Lifang and Irvin, Marguerite R and Kooperberg, Charles and Minster, Ryan L and Mitchell, Braxton D and Nouraie, Mehdi and Psaty, Bruce M and Raffield, Laura M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Benjamin Shoemaker, M and Smith, Nicholas L and Taylor, Kent D and Telen, Marilyn J and Weiss, Scott T and Zhang, Yingze and Heard-Costa, Nancy and Sun, Yan V and Lin, Xihong and Cupples, L Adrienne and Lange, Leslie A and Liu, Ching-Ti and Loos, Ruth J F and North, Kari E and Justice, Anne E} }