@article {8774, title = {Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 06 09}, pages = {3505}, abstract = {

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1\% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60\% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

}, keywords = {Adult, Biological Variation, Population, Biomarkers, Diabetes Mellitus, Type 2, Dyslipidemias, Exome, Genetic Predisposition to Disease, Genotype, Humans, Multifactorial Inheritance, Penetrance, Risk Assessment}, issn = {2041-1723}, doi = {10.1038/s41467-021-23556-4}, author = {Goodrich, Julia K and Singer-Berk, Moriel and Son, Rachel and Sveden, Abigail and Wood, Jordan and England, Eleina and Cole, Joanne B and Weisburd, Ben and Watts, Nick and Caulkins, Lizz and Dornbos, Peter and Koesterer, Ryan and Zappala, Zachary and Zhang, Haichen and Maloney, Kristin A and Dahl, Andy and Aguilar-Salinas, Carlos A and Atzmon, Gil and Barajas-Olmos, Francisco and Barzilai, Nir and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Centeno-Cruz, Federico and Chambers, John C and Chami, Nathalie and Chan, Edmund and Chan, Juliana and Cheng, Ching-Yu and Cho, Yoon Shin and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio and Correa, Adolfo and DeFronzo, Ralph A and Duggirala, Ravindranath and Dupuis, Jos{\'e}e and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Gieger, Christian and Glaser, Benjamin and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez, Ma Elena and Grarup, Niels and Groop, Leif and Gross, Myron and Haiman, Christopher and Han, Sohee and Hanis, Craig L and Hansen, Torben and Heard-Costa, Nancy L and Henderson, Brian E and Hernandez, Juan Manuel Malacara and Hwang, Mi Yeong and Islas-Andrade, Sergio and J{\o}rgensen, Marit E and Kang, Hyun Min and Kim, Bong-Jo and Kim, Young Jin and Koistinen, Heikki A and Kooner, Jaspal Singh and Kuusisto, Johanna and Kwak, Soo-Heon and Laakso, Markku and Lange, Leslie and Lee, Jong-Young and Lee, Juyoung and Lehman, Donna M and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lyssenko, Valeriya and Ma, Ronald C W and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Meigs, James B and Meitinger, Thomas and Mendoza-Caamal, Elvia and Mohlke, Karen L and Morris, Andrew D and Morrison, Alanna C and Ng, Maggie C Y and Nilsson, Peter M and O{\textquoteright}Donnell, Christopher J and Orozco, Lorena and Palmer, Colin N A and Park, Kyong Soo and Post, Wendy S and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Rotter, Jerome I and Saleheen, Danish and Schurmann, Claudia and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Spector, Timothy D and Strauch, Konstantin and Strom, Tim M and Tai, E Shyong and Tam, Claudia H T and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tracy, Russell P and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and van Dam, Rob M and Vasan, Ramachandran S and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Burtt, Noel P and Zaitlen, Noah and McCarthy, Mark I and Boehnke, Michael and Pollin, Toni I and Flannick, Jason and Mercader, Josep M and O{\textquoteright}Donnell-Luria, Anne and Baxter, Samantha and Florez, Jose C and MacArthur, Daniel G and Udler, Miriam S} } @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 {9109, title = {The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.}, journal = {Front Endocrinol (Lausanne)}, volume = {13}, year = {2022}, month = {2022}, pages = {863893}, abstract = {

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) >=1\%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI >= 30 kg/m), and extreme obesity (BMI >= 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1\% of variation in BMI, and 18.3\% and 22.5\% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49\%, and 2.97\% and 3.68\%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24\% for obesity and 0.51\% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.

}, keywords = {Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Obesity, Whole Genome Sequencing}, issn = {1664-2392}, doi = {10.3389/fendo.2022.863893}, author = {Wang, Zhe and Choi, Shing Wan and Chami, Nathalie and Boerwinkle, Eric and Fornage, Myriam and Redline, Susan and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Kim, Wonji and McDonald, Merry-Lynn N and Regan, Elizabeth A and Silverman, Edwin K and Liu, Ching-Ti and Vasan, Ramachandran S and Kalyani, Rita R and Mathias, Rasika A and Yanek, Lisa R and Arnett, Donna K and Justice, Anne E and North, Kari E and Kaplan, Robert and Heckbert, Susan R and de Andrade, Mariza and Guo, Xiuqing and Lange, Leslie A and Rich, Stephen S and Rotter, Jerome I and Ellinor, Patrick T and Lubitz, Steven A and Blangero, John and Shoemaker, M Benjamin and Darbar, Dawood and Gladwin, Mark T and Albert, Christine M and Chasman, Daniel I and Jackson, Rebecca D and Kooperberg, Charles and Reiner, Alexander P and O{\textquoteright}Reilly, Paul F and Loos, Ruth J F} } @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 {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 {9914, title = {Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {539-547}, abstract = {

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

}, keywords = {Atrial Fibrillation, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-024-02072-3}, author = {Roselli, Carolina and Surakka, Ida and Olesen, Morten S and Sveinbjornsson, Gardar and Marston, Nicholas A and Choi, Seung Hoan and Holm, Hilma and Chaffin, Mark and Gudbjartsson, Daniel and Hill, Matthew C and Aegisdottir, Hildur and Albert, Christine M and Alonso, Alvaro and Anderson, Christopher D and Arking, Dan E and Arnar, David O and Barnard, John and Benjamin, Emelia J and Braunwald, Eugene and Brumpton, Ben and Campbell, Archie and Chami, Nathalie and Chasman, Daniel I and Cho, Kelly and Choi, Eue-Keun and Christophersen, Ingrid E and Chung, Mina K and Conen, David and Crijns, Harry J and Cutler, Michael J and Czuba, Tomasz and Damrauer, Scott M and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton and Duong, ThuyVy and Erikstrup, Christian and Esko, T{\~o}nu and Fatkin, Diane and Faul, Jessica D and Ferreira, Manuel and Freitag, Daniel F and Ganesh, Santhi K and Gaziano, J Michael and Geelhoed, Bastiaan and Ghouse, Jonas and Gieger, Christian and Giulianini, Franco and Graham, Sarah E and Gudnason, Vilmundur and Guo, Xiuqing and Haggerty, Christopher and Hayward, Caroline and Heckbert, Susan R and Hveem, Kristian and Ito, Kaoru and Johnson, Renee and Jukema, J Wouter and Jurgens, Sean J and K{\"a}{\"a}b, Stefan and Kane, John P and Kany, Shinwan and Kardia, Sharon L R and Kavousi, Maryam and Khurshid, Shaan and Kamanu, Frederick K and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Komuro, Issei and Krieger, Jose E and Launer, Lenore J and Li, Dadong and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lotta, Luca and Lubitz, Steven A and Lunetta, Kathryn L and Macfarlane, Peter W and Magnusson, Patrik K E and Malik, Rainer and Mantineo, Helene and Marcus, Gregory M and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Melloni, Giorgio E M and Meyre, Pascal B and Miyazawa, Kazuo and Mohanty, Sanghamitra and Monfort, Laia M and M{\"u}ller-Nurasyid, Martina and Nafissi, Navid A and Natale, Andrea and Nazarian, Saman and Ostrowski, Sisse R and Pak, Hui-Nam and Pang, Shichao and Pedersen, Ole B and Pedersen, Nancy L and Pereira, Alexandre C and Pirruccello, James P and Preuss, Michael and Psaty, Bruce M and Pullinger, Clive R and Rader, Daniel J and R{\"a}m{\"o}, Joel T and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rotter, Jerome I and Sabatine, Marc S and Schunkert, Heribert and Shah, Svati H and Shim, Jaemin and Shoemaker, M Benjamin and Simonson, Bridget and Sinner, Moritz F and Smit, Roelof A J and Smith, Jennifer A and Smith, Nicholas L and Smith, J Gustav and Soliman, Elsayed Z and S{\o}rensen, Erik and Sotoodehnia, Nona and Strbian, Daniel and Stricker, Bruno H and Teder-Laving, Maris and Sun, Yan V and Th{\'e}riault, S{\'e}bastien and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Tveit, Arnljot and van der Harst, Pim and van Meurs, Joyce and Wang, Biqi and Weiss, Stefan and Wells, Quinn S and Weng, Lu-Chen and Wilson, Peter W and Xiao, Ling and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Zhao, Wei and Zhou, Xiang and Z{\"o}llner, Sebastian and Ruff, Christian T and Bundgaard, Henning and Willer, Cristen and Stefansson, Kari and Ellinor, Patrick T} } @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} }