@article {1218, title = {Genetic ancestry in lung-function predictions.}, journal = {N Engl J Med}, volume = {363}, year = {2010}, month = {2010 Jul 22}, pages = {321-30}, abstract = {

BACKGROUND: Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.

METHODS: We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.

RESULTS: African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5\% of participants.

CONCLUSIONS: Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)

}, keywords = {Adolescent, Adult, African Americans, Aged, Aged, 80 and over, Female, Forced Expiratory Volume, Genetic Markers, Genotype, Humans, Linear Models, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Reference Values, Respiratory Function Tests, Vital Capacity, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa0907897}, author = {Kumar, Rajesh and Seibold, Max A and Aldrich, Melinda C and Williams, L Keoki and Reiner, Alex P and Colangelo, Laura and Galanter, Joshua and Gignoux, Christopher and Hu, Donglei and Sen, Saunak and Choudhry, Shweta and Peterson, Edward L and Rodriguez-Santana, Jose and Rodriguez-Cintron, William and Nalls, Michael A and Leak, Tennille S and O{\textquoteright}Meara, Ellen and Meibohm, Bernd and Kritchevsky, Stephen B and Li, Rongling and Harris, Tamara B and Nickerson, Deborah A and Fornage, Myriam and Enright, Paul and Ziv, Elad and Smith, Lewis J and Liu, Kiang and Burchard, Esteban Gonz{\'a}lez} } @article {6582, title = {Genome-wide association analysis identifies six new loci associated with forced vital capacity.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jul}, pages = {669-77}, abstract = {

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 {\texttimes} 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

}, keywords = {Cohort Studies, Databases, Genetic, Follow-Up Studies, Forced Expiratory Volume, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung Diseases, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Respiratory Function Tests, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.3011}, author = {Loth, Daan W and Soler Artigas, Maria and Gharib, Sina A and Wain, Louise V and Franceschini, Nora and Koch, Beate and Pottinger, Tess D and Smith, Albert Vernon and Duan, Qing and Oldmeadow, Chris and Lee, Mi Kyeong and Strachan, David P and James, Alan L and Huffman, Jennifer E and Vitart, Veronique and Ramasamy, Adaikalavan and Wareham, Nicholas J and Kaprio, Jaakko and Wang, Xin-Qun and Trochet, Holly and K{\"a}h{\"o}nen, Mika and Flexeder, Claudia and Albrecht, Eva and Lopez, Lorna M and de Jong, Kim and Thyagarajan, Bharat and Alves, Alexessander Couto and Enroth, Stefan and Omenaas, Ernst and Joshi, Peter K and Fall, Tove and Vi{\~n}uela, Ana and Launer, Lenore J and Loehr, Laura R and Fornage, Myriam and Li, Guo and Wilk, Jemma B and Tang, Wenbo and Manichaikul, Ani and Lahousse, Lies and Harris, Tamara B and North, Kari E and Rudnicka, Alicja R and Hui, Jennie and Gu, Xiangjun and Lumley, Thomas and Wright, Alan F and Hastie, Nicholas D and Campbell, Susan and Kumar, Rajesh and Pin, Isabelle and Scott, Robert A and Pietil{\"a}inen, Kirsi H and Surakka, Ida and Liu, Yongmei and Holliday, Elizabeth G and Schulz, Holger and Heinrich, Joachim and Davies, Gail and Vonk, Judith M and Wojczynski, Mary and Pouta, Anneli and Johansson, Asa and Wild, Sarah H and Ingelsson, Erik and Rivadeneira, Fernando and V{\"o}lzke, Henry and Hysi, Pirro G and Eiriksdottir, Gudny and Morrison, Alanna C and Rotter, Jerome I and Gao, Wei and Postma, Dirkje S and White, Wendy B and Rich, Stephen S and Hofman, Albert and Aspelund, Thor and Couper, David and Smith, Lewis J and Psaty, Bruce M and Lohman, Kurt and Burchard, Esteban G and Uitterlinden, Andr{\'e} G and Garcia, Melissa and Joubert, Bonnie R and McArdle, Wendy L and Musk, A Bill and Hansel, Nadia and Heckbert, Susan R and Zgaga, Lina and van Meurs, Joyce B J and Navarro, Pau and Rudan, Igor and Oh, Yeon-Mok and Redline, Susan and Jarvis, Deborah L and Zhao, Jing Hua and Rantanen, Taina and O{\textquoteright}Connor, George T and Ripatti, Samuli and Scott, Rodney J and Karrasch, Stefan and Grallert, Harald and Gaddis, Nathan C and Starr, John M and Wijmenga, Cisca and Minster, Ryan L and Lederer, David J and Pekkanen, Juha and Gyllensten, Ulf and Campbell, Harry and Morris, Andrew P and Gl{\"a}ser, Sven and Hammond, Christopher J and Burkart, Kristin M and Beilby, John and Kritchevsky, Stephen B and Gudnason, Vilmundur and Hancock, Dana B and Williams, O Dale and Polasek, Ozren and Zemunik, Tatijana and Kolcic, Ivana and Petrini, Marcy F and Wjst, Matthias and Kim, Woo Jin and Porteous, David J and Scotland, Generation and Smith, Blair H and Viljanen, Anne and Heli{\"o}vaara, Markku and Attia, John R and Sayers, Ian and Hampel, Regina and Gieger, Christian and Deary, Ian J and Boezen, H Marike and Newman, Anne and Jarvelin, Marjo-Riitta and Wilson, James F and Lind, Lars and Stricker, Bruno H and Teumer, Alexander and Spector, Timothy D and Mel{\'e}n, Erik and Peters, Marjolein J and Lange, Leslie A and Barr, R Graham and Bracke, Ken R and Verhamme, Fien M and Sung, Joohon and Hiemstra, Pieter S and Cassano, Patricia A and Sood, Akshay and Hayward, Caroline and Dupuis, Jos{\'e}e and Hall, Ian P and Brusselle, Guy G and Tobin, Martin D and London, Stephanie J} } @article {7558, title = {Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jan}, pages = {42-53}, abstract = {

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

}, issn = {1546-1718}, doi = {10.1038/s41588-017-0014-7}, author = {Demenais, Florence and Margaritte-Jeannin, Patricia and Barnes, Kathleen C and Cookson, William O C and Altm{\"u}ller, Janine and Ang, Wei and Barr, R Graham and Beaty, Terri H and Becker, Allan B and Beilby, John and Bisgaard, Hans and Bjornsdottir, Unnur Steina and Bleecker, Eugene and B{\o}nnelykke, Klaus and Boomsma, Dorret I and Bouzigon, Emmanuelle and Brightling, Christopher E and Brossard, Myriam and Brusselle, Guy G and Burchard, Esteban and Burkart, Kristin M and Bush, Andrew and Chan-Yeung, Moira and Chung, Kian Fan and Couto Alves, Alexessander and Curtin, John A and Custovic, Adnan and Daley, Denise and de Jongste, Johan C and Del-Rio-Navarro, Blanca E and Donohue, Kathleen M and Duijts, Liesbeth and Eng, Celeste and Eriksson, Johan G and Farrall, Martin and Fedorova, Yuliya and Feenstra, Bjarke and Ferreira, Manuel A and Freidin, Maxim B and Gajdos, Zofia and Gauderman, Jim and Gehring, Ulrike and Geller, Frank and Genuneit, Jon and Gharib, Sina A and Gilliland, Frank and Granell, Raquel and Graves, Penelope E and Gudbjartsson, Daniel F and Haahtela, Tari and Heckbert, Susan R and Heederik, Dick and Heinrich, Joachim and Heli{\"o}vaara, Markku and Henderson, John and Himes, Blanca E and Hirose, Hiroshi and Hirschhorn, Joel N and Hofman, Albert and Holt, Patrick and Hottenga, Jouke and Hudson, Thomas J and Hui, Jennie and Imboden, Medea and Ivanov, Vladimir and Jaddoe, Vincent W V and James, Alan and Janson, Christer and Jarvelin, Marjo-Riitta and Jarvis, Deborah and Jones, Graham and Jonsdottir, Ingileif and Jousilahti, Pekka and Kabesch, Michael and K{\"a}h{\"o}nen, Mika and Kantor, David B and Karunas, Alexandra S and Khusnutdinova, Elza and Koppelman, Gerard H and Kozyrskyj, Anita L and Kreiner, Eskil and Kubo, Michiaki and Kumar, Rajesh and Kumar, Ashish and Kuokkanen, Mikko and Lahousse, Lies and Laitinen, Tarja and Laprise, Catherine and Lathrop, Mark and Lau, Susanne and Lee, Young-Ae and Lehtim{\"a}ki, Terho and Letort, S{\'e}bastien and Levin, Albert M and Li, Guo and Liang, Liming and Loehr, Laura R and London, Stephanie J and Loth, Daan W and Manichaikul, Ani and Marenholz, Ingo and Martinez, Fernando J and Matheson, Melanie C and Mathias, Rasika A and Matsumoto, Kenji and Mbarek, Hamdi and McArdle, Wendy L and Melbye, Mads and Mel{\'e}n, Erik and Meyers, Deborah and Michel, Sven and Mohamdi, Hamida and Musk, Arthur W and Myers, Rachel A and Nieuwenhuis, Maartje A E and Noguchi, Emiko and O{\textquoteright}Connor, George T and Ogorodova, Ludmila M and Palmer, Cameron D and Palotie, Aarno and Park, Julie E and Pennell, Craig E and Pershagen, G{\"o}ran and Polonikov, Alexey and Postma, Dirkje S and Probst-Hensch, Nicole and Puzyrev, Valery P and Raby, Benjamin A and Raitakari, Olli T and Ramasamy, Adaikalavan and Rich, Stephen S and Robertson, Colin F and Romieu, Isabelle and Salam, Muhammad T and Salomaa, Veikko and Schl{\"u}nssen, Vivi and Scott, Robert and Selivanova, Polina A and Sigsgaard, Torben and Simpson, Angela and Siroux, Val{\'e}rie and Smith, Lewis J and Solodilova, Maria and Standl, Marie and Stefansson, Kari and Strachan, David P and Stricker, Bruno H and Takahashi, Atsushi and Thompson, Philip J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiesler, Carla M T and Torgerson, Dara G and Tsunoda, Tatsuhiko and Uitterlinden, Andr{\'e} G and van der Valk, Ralf J P and Vaysse, Amaury and Vedantam, Sailaja and von Berg, Andrea and von Mutius, Erika and Vonk, Judith M and Waage, Johannes and Wareham, Nick J and Weiss, Scott T and White, Wendy B and Wickman, Magnus and Widen, Elisabeth and Willemsen, Gonneke and Williams, L Keoki and Wouters, Inge M and Yang, James J and Zhao, Jing Hua and Moffatt, Miriam F and Ober, Carole and Nicolae, Dan L} } @article {9037, title = {Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.}, journal = {Am J Hum Genet}, year = {2022}, month = {2022 Mar 31}, abstract = {

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1~s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR]~= 1.24 [95\% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with >= 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p~<~2.2~{\texttimes}~10 with portability gains ranging from 5\% to 28\%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2022.03.007}, author = {Hu, Xiaowei and Qiao, Dandi and Kim, Wonji and Moll, Matthew and Balte, Pallavi P and Lange, Leslie A and Bartz, Traci M and Kumar, Rajesh and Li, Xingnan and Yu, Bing and Cade, Brian E and Laurie, Cecelia A and Sofer, Tamar and Ruczinski, Ingo and Nickerson, Deborah A and Muzny, Donna M and Metcalf, Ginger A and Doddapaneni, Harshavardhan and Gabriel, Stacy and Gupta, Namrata and Dugan-Perez, Shannon and Cupples, L Adrienne and Loehr, Laura R and Jain, Deepti and Rotter, Jerome I and Wilson, James G and Psaty, Bruce M and Fornage, Myriam and Morrison, Alanna C and Vasan, Ramachandran S and Washko, George and Rich, Stephen S and O{\textquoteright}Connor, George T and Bleecker, Eugene and Kaplan, Robert C and Kalhan, Ravi and Redline, Susan and Gharib, Sina A and Meyers, Deborah and Ortega, Victor and Dupuis, Jos{\'e}e and London, Stephanie J and Lappalainen, Tuuli and Oelsner, Elizabeth C and Silverman, Edwin K and Barr, R Graham and Thornton, Timothy A and Wheeler, Heather E and Cho, Michael H and Im, Hae Kyung and Manichaikul, Ani} } @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} }