Search

Your search keyword '"Chesi, Alessandra"' showing total 377 results
Start Over Author "Chesi, Alessandra"
377 results on '"Chesi, Alessandra"'

2. Author Correction: Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author

Bradfeld, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkhiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithiof-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Kindler, Joseph, Kähönen, Mika, Lanca, Carla, Lappe, Joan, Lee, Nanette R., McCormack, Shana, Mentch, Frank D., Mitchell, Jonathan A., Mononen, Nina, Niinikoski, Harri, Oken, Emily, Pahkala, Katja, Sim, Xueling, Teo, Yik-Ying, Baier, Leslie J., van Beijsterveldt, Toos, Adair, Linda S., Boomsma, Dorret I., de Geus, Eco, Guxens, Mònica, Eriksson, Johan G., Felix, Janine F., Gilliland, Frank D., Hansen, Torben, Hardy, Rebecca, Hivert, Marie-France, Holm, Jens-Christian, Jaddoe, Vincent W. V., Järvelin, Marjo-Riitta, Lehtimäki, Terho, Mackey, David A., Meyre, David, Mohlke, Karen L., Mykkänen, Juha, Oberfeld, Sharon, Pennell, Craig E., Perry, John R. B., Raitakari, Olli, Rivadeneira, Fernando, Saw, Seang-Mei, Sebert, Sylvain, Shepherd, John A., Standl, Marie, Sørensen, Thorkild I. A., Timpson, Nicholas J., Torrent, Maties, Willemsen, Gonneke, Hypponen, Elina, Power, Chris, McCarthy, Mark I., Freathy, Rachel M., Widén, Elisabeth, Hakonarson, Hakon, Prokopenko, Inga, Voight, Benjamin F., Zemel, Babette S., Grant, Struan F. A., and Cousminer, Diana L.

Published
2024
Full Text
View/download PDF

3. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author

Bradfield, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkhiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Kindler, Joseph, Kähönen, Mika, Lanca, Carla, Lappe, Joan, Lee, Nanette R., McCormack, Shana, Mentch, Frank D., Mitchell, Jonathan A., Mononen, Nina, Niinikoski, Harri, Oken, Emily, Pahkala, Katja, Sim, Xueling, Teo, Yik-Ying, Baier, Leslie J., van Beijsterveldt, Toos, Adair, Linda S., Boomsma, Dorret I., de Geus, Eco, Guxens, Mònica, Eriksson, Johan G., Felix, Janine F., Gilliland, Frank D., Biobank, Penn Medicine, Hansen, Torben, Hardy, Rebecca, Hivert, Marie-France, Holm, Jens-Christian, Jaddoe, Vincent W. V., Järvelin, Marjo-Riitta, Lehtimäki, Terho, Mackey, David A., Meyre, David, Mohlke, Karen L., Mykkänen, Juha, Oberfield, Sharon, Pennell, Craig E., Perry, John R. B., Raitakari, Olli, Rivadeneira, Fernando, Saw, Seang-Mei, Sebert, Sylvain, Shepherd, John A., Standl, Marie, Sørensen, Thorkild I. A., Timpson, Nicholas J., Torrent, Maties, Willemsen, Gonneke, Hypponen, Elina, Power, Chris, McCarthy, Mark I., Freathy, Rachel M., Widén, Elisabeth, Hakonarson, Hakon, Prokopenko, Inga, Voight, Benjamin F., Zemel, Babette S., Grant, Struan F. A., and Cousminer, Diana L.

Published
2024
Full Text
View/download PDF

4. A saturated map of common genetic variants associated with human height

Author

Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U, Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D, Graham, Sarah E, Mukamel, Ronen E, Spracklen, Cassandra N, Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H, Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E, Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S, Akiyama, Masato, Allison, Matthew A, Alvarez, Marcus, Andersen, Mette K, Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F, Bollepalli, Sailalitha, Bonnycastle, Lori L, Bork-Jensen, Jette, Bradfield, Jonathan P, Bradford, Yuki, Braund, Peter S, Brody, Jennifer A, Burgdorf, Kristoffer S, Cade, Brian E, Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E Warwick, Degenhard, Frauke, Delgado, Graciela E, Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B, Engmann, Jorgen E, Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D, Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E, Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P, Goel, Anuj, Gordon, Scott D, Gorski, Mathias, Grove, Jakob, and Guo, Xiuqing

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Humans, Body Height, Gene Frequency, Genome, Human, Genome-Wide Association Study, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Europe, Sample Size, Phenotype, Chromosome Mapping, 23andMe Research Team, VA Million Veteran Program, DiscovEHR, eMERGE, Lifelines Cohort Study, PRACTICAL Consortium, Understanding Society Scientific Group, General Science & Technology
Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022

5. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Author

Ramdas, Shweta, Judd, Jonathan, Graham, Sarah E, Kanoni, Stavroula, Wang, Yuxuan, Surakka, Ida, Wenz, Brandon, Clarke, Shoa L, Chesi, Alessandra, Wells, Andrew, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg JM, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, QiPing, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Lee, Wen-Jane, Hsiung, Chao Agnes, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, and Sabater-Lleal, Maria

Subjects
Human Genome, Biotechnology, Genetics, 2.1 Biological and endogenous factors, Aetiology, Chromatin, Genome-Wide Association Study, Genomics, Humans, Lipids, Polymorphism, Single Nucleotide, Million Veterans Program, Global Lipids Genetics Consortium, complex traits, fine-mapping, functional genomics, lipid biology, post-GWAS, regulatory mechanism, variant prioritization, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Published
2022

6. Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3′ UTR of FAIM2

Author

Littleton, Sheridan H., Trang, Khanh B., Volpe, Christina M., Cook, Kieona, DeBruyne, Nicole, Maguire, Jean Ann, Weidekamp, Mary Ann, Hodge, Kenyaita M., Boehm, Keith, Lu, Sumei, Chesi, Alessandra, Bradfield, Jonathan P., Pippin, James A., Anderson, Stewart A., Wells, Andrew D., Pahl, Matthew C., and Grant, Struan F.A.

Published
2024
Full Text
View/download PDF

7. Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry

Author

Graff, Mariaelisa, Justice, Anne E, Young, Kristin L, Marouli, Eirini, Zhang, Xinruo, Fine, Rebecca S, Lim, Elise, Buchanan, Victoria, Rand, Kristin, Feitosa, Mary F, Wojczynski, Mary K, Yanek, Lisa R, Shao, Yaming, Rohde, Rebecca, Adeyemo, Adebowale A, Aldrich, Melinda C, Allison, Matthew A, Ambrosone, Christine B, Ambs, Stefan, Amos, Christopher, Arnett, Donna K, Atwood, Larry, Bandera, Elisa V, Bartz, Traci, Becker, Diane M, Berndt, Sonja I, Bernstein, Leslie, Bielak, Lawrence F, Blot, William J, Bottinger, Erwin P, Bowden, Donald W, Bradfield, Jonathan P, Brody, Jennifer A, Broeckel, Ulrich, Burke, Gregory, Cade, Brian E, Cai, Qiuyin, Caporaso, Neil, Carlson, Chris, Carpten, John, Casey, Graham, Chanock, Stephen J, Chen, Guanjie, Chen, Minhui, Chen, Yii-Der I, Chen, Wei-Min, Chesi, Alessandra, Chiang, Charleston WK, Chu, Lisa, Coetzee, Gerry A, Conti, David V, Cooper, Richard S, Cushman, Mary, Demerath, Ellen, Deming, Sandra L, Dimitrov, Latchezar, Ding, Jingzhong, Diver, W Ryan, Duan, Qing, Evans, Michele K, Falusi, Adeyinka G, Faul, Jessica D, Fornage, Myriam, Fox, Caroline, Freedman, Barry I, Garcia, Melissa, Gillanders, Elizabeth M, Goodman, Phyllis, Gottesman, Omri, Grant, Struan FA, Guo, Xiuqing, Hakonarson, Hakon, Haritunians, Talin, Harris, Tamara B, Harris, Curtis C, Henderson, Brian E, Hennis, Anselm, Hernandez, Dena G, Hirschhorn, Joel N, McNeill, Lorna Haughton, Howard, Timothy D, Howard, Barbara, Hsing, Ann W, Hsu, Yu-Han H, Hu, Jennifer J, Huff, Chad D, Huo, Dezheng, Ingles, Sue A, Irvin, Marguerite R, John, Esther M, Johnson, Karen C, Jordan, Joanne M, Kabagambe, Edmond K, Kang, Sun J, Kardia, Sharon L, Keating, Brendan J, Kittles, Rick A, Klein, Eric A, Kolb, Suzanne, and Kolonel, Laurence N

Subjects
Human Genome, Genetics, Africa, Black or African American, Black People, Body Height, Europe, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, African ancestry, fine-mapping, genome-wide, height, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Published
2021

9. A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR

Author

Xu, Mai, Mehl, Lindsey, Zhang, Tongwu, Thakur, Rohit, Sowards, Hayley, Myers, Timothy, Jessop, Lea, Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Michael, Helen T., Bunda, Patricia, Jones, Kristine, Higson, Herbert, Hennessey, Rebecca C., Jermusyk, Ashley, Kovacs, Michael A., Landi, Maria Teresa, Iles, Mark M., Goldstein, Alisa M., Choi, Jiyeon, Chanock, Stephen J., Grant, Struan F.A., Chari, Raj, Merlino, Glenn, Law, Matthew H., and Brown, Kevin M.

Published
2021
Full Text
View/download PDF

10. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Author

Medina-Gomez, Carolina, Kemp, John P, Trajanoska, Katerina, Luan, Jian’an, Chesi, Alessandra, Ahluwalia, Tarunveer S, Mook-Kanamori, Dennis O, Ham, Annelies, Hartwig, Fernando P, Evans, Daniel S, Joro, Raimo, Nedeljkovic, Ivana, Zheng, Hou-Feng, Zhu, Kun, Atalay, Mustafa, Liu, Ching-Ti, Nethander, Maria, Broer, Linda, Porleifsson, Gudmar, Mullin, Benjamin H, Handelman, Samuel K, Nalls, Mike A, Jessen, Leon E, Heppe, Denise HM, Richards, J Brent, Wang, Carol, Chawes, Bo, Schraut, Katharina E, Amin, Najaf, Wareham, Nick, Karasik, David, Van der Velde, Nathalie, Ikram, M Arfan, Zemel, Babette S, Zhou, Yanhua, Carlsson, Christian J, Liu, Yongmei, McGuigan, Fiona E, Boer, Cindy G, Bønnelykke, Klaus, Ralston, Stuart H, Robbins, John A, Walsh, John P, Zillikens, M Carola, Langenberg, Claudia, Li-Gao, Ruifang, Williams, Frances MK, Harris, Tamara B, Akesson, Kristina, Jackson, Rebecca D, Sigurdsson, Gunnar, Heijer, Martin den, van der Eerden, Bram CJ, van de Peppel, Jeroen, Spector, Timothy D, Pennell, Craig, Horta, Bernardo L, Felix, Janine F, Zhao, Jing Hua, Wilson, Scott G, de Mutsert, Renée, Bisgaard, Hans, Styrkársdóttir, Unnur, Jaddoe, Vincent W, Orwoll, Eric, Lakka, Timo A, Scott, Robert, Grant, Struan FA, Lorentzon, Mattias, van Duijn, Cornelia M, Wilson, James F, Stefansson, Kari, Psaty, Bruce M, Kiel, Douglas P, Ohlsson, Claes, Ntzani, Evangelia, van Wijnen, Andre J, Forgetta, Vincenzo, Ghanbari, Mohsen, Logan, John G, Williams, Graham R, Bassett, JH Duncan, Croucher, Peter I, Evangelou, Evangelos, Uitterlinden, Andre G, Ackert-Bicknell, Cheryl L, Tobias, Jonathan H, Evans, David M, and Rivadeneira, Fernando

Subjects
Rare Diseases, Aging, Human Genome, Osteoporosis, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Good Health and Well Being, Adolescent, Age Factors, Animals, Bone Density, Child, Child, Preschool, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Regression Analysis, BMD, CREB3L1, ESR1, GWASs, RANKL, age-dependent effects, bone mineral density, fracture, genetic correlation, genome-wide association studies, meta-regression, total-body DXA, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Published
2018

12. Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

Author

Ng, Maggie CY, Graff, Mariaelisa, Lu, Yingchang, Justice, Anne E, Mudgal, Poorva, Liu, Ching-Ti, Young, Kristin, Yanek, Lisa R, Feitosa, Mary F, Wojczynski, Mary K, Rand, Kristin, Brody, Jennifer A, Cade, Brian E, Dimitrov, Latchezar, Duan, Qing, Guo, Xiuqing, Lange, Leslie A, Nalls, Michael A, Okut, Hayrettin, Tajuddin, Salman M, Tayo, Bamidele O, Vedantam, Sailaja, Bradfield, Jonathan P, Chen, Guanjie, Chen, Wei-Min, Chesi, Alessandra, Irvin, Marguerite R, Padhukasahasram, Badri, Smith, Jennifer A, Zheng, Wei, Allison, Matthew A, Ambrosone, Christine B, Bandera, Elisa V, Bartz, Traci M, Berndt, Sonja I, Bernstein, Leslie, Blot, William J, Bottinger, Erwin P, Carpten, John, Chanock, Stephen J, Chen, Yii-Der Ida, Conti, David V, Cooper, Richard S, Fornage, Myriam, Freedman, Barry I, Garcia, Melissa, Goodman, Phyllis J, Hsu, Yu-Han H, Hu, Jennifer, Huff, Chad D, Ingles, Sue A, John, Esther M, Kittles, Rick, Klein, Eric, Li, Jin, McKnight, Barbara, Nayak, Uma, Nemesure, Barbara, Ogunniyi, Adesola, Olshan, Andrew, Press, Michael F, Rohde, Rebecca, Rybicki, Benjamin A, Salako, Babatunde, Sanderson, Maureen, Shao, Yaming, Siscovick, David S, Stanford, Janet L, Stevens, Victoria L, Stram, Alex, Strom, Sara S, Vaidya, Dhananjay, Witte, John S, Yao, Jie, Zhu, Xiaofeng, Ziegler, Regina G, Zonderman, Alan B, Adeyemo, Adebowale, Ambs, Stefan, Cushman, Mary, Faul, Jessica D, Hakonarson, Hakon, Levin, Albert M, Nathanson, Katherine L, Ware, Erin B, Weir, David R, Zhao, Wei, Zhi, Degui, Bone Mineral Density in Childhood Study (BMDCS) Group, Arnett, Donna K, Grant, Struan FA, Kardia, Sharon LR, Oloapde, Olufunmilayo I, Rao, DC, Rotimi, Charles N, Sale, Michele M, Williams, L Keoki, Zemel, Babette S, Becker, Diane M, and Borecki, Ingrid B

Subjects
Bone Mineral Density in Childhood Study (BMDCS) Group, Humans, Obesity, Genetic Predisposition to Disease, Serine Endopeptidases, Anthropometry, Body Mass Index, Waist-Hip Ratio, Chromosome Mapping, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Adiposity, Genome-Wide Association Study, Transcription Factor 7-Like 2 Protein, Genetics, Human Genome, 2.1 Biological and endogenous factors, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (

Published
2017

14. Osteoporosis GWAS-implicated DNM3 locus contextually regulates osteoblastic and chondrogenic fate of mesenchymal stem/progenitor cells through oscillating miR-199a-5p levels

Author

Kaur, Gurcharan, primary, Pippin, James A, additional, Chang, Solomon, additional, Redmond, Justin, additional, Chesi, Alessandra, additional, Wells, Andrew D, additional, Maerz, Tristan, additional, Grant, Struan F A, additional, Coleman, Rhima M, additional, Hankenson, Kurt D, additional, and Wagley, Yadav, additional

Published
2024
Full Text
View/download PDF

16. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author

Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, Cousminer, Diana L, Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, and Cousminer, Diana L

Abstract

Background: Pubertal growth patterns correlate with future health outcomes. How‑ever, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Transla‑tion And Rotation (SITAR) growth curve analysis on~56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analy‑ses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results: Large-scale growth modeling enables an unprecedented view of adoles‑ cent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide signifcant loci and leverage trans-ancestry data to perform fnemapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with diferent growth trajectories correlated with dif‑ferent outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fbrillation. Conclusion: We report novel genetic associations with the tempo of pubertal growth and fnd that genetic determinants of growth are correlated with reproductive, glyce‑mic, respiratory, and cardiac traits in adulthood. These results aid in identifying specifc growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern., BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

Published
2024

17. Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits

Author

Pahl, Matthew C., Doege, Claudia A., Hodge, Kenyaita M., Littleton, Sheridan H., Leonard, Michelle E., Lu, Sumei, Rausch, Rick, Pippin, James A., De Rosa, Maria Caterina, Basak, Alisha, Bradfield, Jonathan P., Hammond, Reza K., Boehm, Keith, Berkowitz, Robert I., Lasconi, Chiara, Su, Chun, Chesi, Alessandra, Johnson, Matthew E., Wells, Andrew D., Voight, Benjamin F., Leibel, Rudolph L., Cousminer, Diana L., and Grant, Struan F. A.

Published
2021
Full Text
View/download PDF

18. CYP11B1 variants influence skeletal maturation via alternative splicing

Author

Grgic, Olja, Gazzara, Matthew R., Chesi, Alessandra, Medina-Gomez, Carolina, Cousminer, Diana L., Mitchell, Jonathan A., Prijatelj, Vid, de Vries, Jard, Shevroja, Enisa, McCormack, Shana E., Kalkwarf, Heidi J., Lappe, Joan M., Gilsanz, Vicente, Oberfield, Sharon E., Shepherd, John A., Kelly, Andrea, Mahboubi, Soroosh, Faucz, Fabio R., Feelders, Richard A., de Jong, Frank H., Uitterlinden, Andre G., Visser, Jenny A., Ghanem, Louis R., Wolvius, Eppo B., Hofland, Leo J., Stratakis, Constantine A., Zemel, Babette S., Barash, Yoseph, Grant, Struan F. A., and Rivadeneira, Fernando

Published
2021
Full Text
View/download PDF

19. Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual

Author

Cousminer, Diana L., Wagley, Yadav, Pippin, James A., Elhakeem, Ahmed, Way, Gregory P., Pahl, Matthew C., McCormack, Shana E., Chesi, Alessandra, Mitchell, Jonathan A., Kindler, Joseph M., Baird, Denis, Hartley, April, Howe, Laura, Kalkwarf, Heidi J., Lappe, Joan M., Lu, Sumei, Leonard, Michelle E., Johnson, Matthew E., Hakonarson, Hakon, Gilsanz, Vicente, Shepherd, John A., Oberfield, Sharon E., Greene, Casey S., Kelly, Andrea, Lawlor, Deborah A., Voight, Benjamin F., Wells, Andrew D., Zemel, Babette S., Hankenson, Kurt D., and Grant, Struan F. A.

Published
2021
Full Text
View/download PDF

20. Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver

Author

Çalışkan, Minal, Manduchi, Elisabetta, Rao, H. Shanker, Segert, Julian A., Beltrame, Marcia Holsbach, Trizzino, Marco, Park, YoSon, Baker, Samuel W., Chesi, Alessandra, Johnson, Matthew E., Hodge, Kenyaita M., Leonard, Michelle E., Loza, Baoli, Xin, Dong, Berrido, Andrea M., Hand, Nicholas J., Bauer, Robert C., Wells, Andrew D., Olthoff, Kim M., Shaked, Abraham, Rader, Daniel J., Grant, Struan F.A., and Brown, Christopher D.

Published
2019
Full Text
View/download PDF

21. Perturbation of the insomnia WDR90 genome-wide association studies locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q.

Author

Sonti, Shilpa, Littleton, Sheridan H, Pahl, Matthew C, Zimmerman, Amber J, Chesi, Alessandra, Palermo, Justin, Lasconi, Chiara, Brown, Elizabeth B, Pippin, James A, Wells, Andrew D, Doldur-Balli, Fusun, Pack, Allan I, Gehrman, Phillip R, Keene, Alex C, and Grant, Struan F A

Published
2024
Full Text
View/download PDF

25. 3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity

Author

Trang, Khanh B, primary, Pahl, Matthew C, additional, Pippin, James A, additional, Su, Chun, additional, Littleton, Sheridan H, additional, Sharma, Prabhat, additional, Kulkarni, Nikhil N, additional, Ghanem, Louis R, additional, Terry, Natalie A, additional, O'Brien, Joan M, additional, Wagley, Yadav, additional, Hankenson, Kurt D, additional, Jermusyk, Ashley, additional, Hoskins, Jason W, additional, Amundadottir, Laufey T, additional, Xu, Mai, additional, Brown, Kevin M, additional, Anderson, Stewart A, additional, Yang, Wenli, additional, Titchenell, Paul M, additional, Seale, Patrick, additional, Cook, Laura, additional, Levings, Megan K, additional, Zemel, Babette S, additional, Chesi, Alessandra, additional, Wells, Andrew D, additional, and Grant, Struan FA, additional

Published
2023
Full Text
View/download PDF

26. Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3′ UTR ofFAIM2

Author

Littleton, Sheridan H, primary, Trang, Khanh B, additional, Volpe, Christina M, additional, Cook, Kieona, additional, DeBruyne, Nicole, additional, Maguire, Jean Ann, additional, Weidekamp, Mary Ann, additional, Boehm, Keith, additional, Chesi, Alessandra, additional, Pippin, James A, additional, Anderson, Stewart A, additional, Wells, Andrew D, additional, Pahl, Matthew C, additional, and Grant, Struan FA, additional

Published
2023
Full Text
View/download PDF

27. Perturbation of the insomnia WDR90 GWAS locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q

Author

SONTI, SHILPA, primary, Littleton, Sheridan H, additional, Pahl, Matthew C, additional, Zimmerman, Amber J, additional, Chesi, Alessandra, additional, Palermo, Justin, additional, Lasconi, Chiara, additional, Brown, Elizabeth B, additional, Pippin, James A, additional, Wells, Andrew D, additional, Balli, Fusun Doldur, additional, Pack, Allan I, additional, Gehrman, Philip R, additional, Keen, Alex C, additional, and Grant, Struan FA, additional

Published
2023
Full Text
View/download PDF

28. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis

Author

Medina-Gomez, Carolina, primary, Mullin, Benjamin H., additional, Chesi, Alessandra, additional, Prijatelj, Vid, additional, Kemp, John P., additional, Shochat-Carvalho, Chen, additional, Trajanoska, Katerina, additional, Wang, Carol, additional, Joro, Raimo, additional, Evans, Tavia E., additional, Schraut, Katharina E., additional, Li-Gao, Ruifang, additional, Ahluwalia, Tarunveer S., additional, Zillikens, M. Carola, additional, Zhu, Kun, additional, Mook-Kanamori, Dennis O., additional, Evans, Daniel S., additional, Nethander, Maria, additional, Knol, Maria J., additional, Thorleifsson, Gudmar, additional, Prokic, Ivana, additional, Zemel, Babette, additional, Broer, Linda, additional, McGuigan, Fiona E., additional, van Schoor, Natasja M., additional, Reppe, Sjur, additional, Pawlak, Mikolaj A., additional, Ralston, Stuart H., additional, van der Velde, Nathalie, additional, Lorentzon, Mattias, additional, Stefansson, Kari, additional, Adams, Hieab H. H., additional, Wilson, Scott G., additional, Ikram, M. Arfan, additional, Walsh, John P., additional, Lakka, Timo A., additional, Gautvik, Kaare M., additional, Wilson, James F., additional, Orwoll, Eric S., additional, van Duijn, Cornelia M., additional, Bønnelykke, Klaus, additional, Uitterlinden, Andre G., additional, Styrkársdóttir, Unnur, additional, Akesson, Kristina E., additional, Spector, Timothy D., additional, Tobias, Jonathan H., additional, Ohlsson, Claes, additional, Felix, Janine F., additional, Bisgaard, Hans, additional, Grant, Struan F. A., additional, Richards, J. Brent, additional, Evans, David M., additional, van der Eerden, Bram, additional, van de Peppel, Jeroen, additional, Ackert-Bicknell, Cheryl, additional, Karasik, David, additional, Kague, Erika, additional, and Rivadeneira, Fernando, additional

Published
2023
Full Text
View/download PDF

30. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis

Author

Medina-Gomez, Carolina, Mullin, Benjamin H., Chesi, Alessandra, Prijatelj, Vid, Kemp, John P., Shochat-Carvalho, Chen, Trajanoska, Katerina, Wang, Carol, Joro, Raimo, Evans, Tavia E., Schraut, Katharina E., Li-Gao, Ruifang, Ahluwalia, Tarunveer S., Zillikens, M. Carola, Zhu, Kun, Mook-Kanamori, Dennis O., Evans, Daniel S., Nethander, Maria, Knol, Maria J., Thorleifsson, Gudmar, Prokic, Ivana, Zemel, Babette, Broer, Linda, McGuigan, Fiona E., van Schoor, Natasja M., Reppe, Sjur, Pawlak, Mikolaj A., Ralston, Stuart H., van der Velde, Nathalie, Lorentzon, Mattias, Stefansson, Kari, Adams, Hieab H.H., Wilson, Scott G., Ikram, M. Arfan, Walsh, John P., Lakka, Timo A., Gautvik, Kaare M., Wilson, James F., Orwoll, Eric S., van Duijn, Cornelia M., Bønnelykke, Klaus, Uitterlinden, Andre G., Styrkársdóttir, Unnur, Akesson, Kristina E., Spector, Timothy D., Tobias, Jonathan H., Ohlsson, Claes, Felix, Janine F., Bisgaard, Hans, Grant, Struan F.A., Richards, J. Brent, Evans, David M., van der Eerden, Bram, van de Peppel, Jeroen, Ackert-Bicknell, Cheryl, Karasik, David, Kague, Erika, Rivadeneira, Fernando, Medina-Gomez, Carolina, Mullin, Benjamin H., Chesi, Alessandra, Prijatelj, Vid, Kemp, John P., Shochat-Carvalho, Chen, Trajanoska, Katerina, Wang, Carol, Joro, Raimo, Evans, Tavia E., Schraut, Katharina E., Li-Gao, Ruifang, Ahluwalia, Tarunveer S., Zillikens, M. Carola, Zhu, Kun, Mook-Kanamori, Dennis O., Evans, Daniel S., Nethander, Maria, Knol, Maria J., Thorleifsson, Gudmar, Prokic, Ivana, Zemel, Babette, Broer, Linda, McGuigan, Fiona E., van Schoor, Natasja M., Reppe, Sjur, Pawlak, Mikolaj A., Ralston, Stuart H., van der Velde, Nathalie, Lorentzon, Mattias, Stefansson, Kari, Adams, Hieab H.H., Wilson, Scott G., Ikram, M. Arfan, Walsh, John P., Lakka, Timo A., Gautvik, Kaare M., Wilson, James F., Orwoll, Eric S., van Duijn, Cornelia M., Bønnelykke, Klaus, Uitterlinden, Andre G., Styrkársdóttir, Unnur, Akesson, Kristina E., Spector, Timothy D., Tobias, Jonathan H., Ohlsson, Claes, Felix, Janine F., Bisgaard, Hans, Grant, Struan F.A., Richards, J. Brent, Evans, David M., van der Eerden, Bram, van de Peppel, Jeroen, Ackert-Bicknell, Cheryl, Karasik, David, Kague, Erika, and Rivadeneira, Fernando

Abstract

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases., Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.

Published
2023

32. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Author

FALS Sequencing Consortium, Cirulli, Elizabeth T., Lasseigne, Brittany N., Petrovski, Slavé, Sapp, Peter C., Dion, Patrick A., Leblond, Claire S., Couthouis, Julien, Lu, Yi-Fan, Wang, Quanli, Krueger, Brian J., Ren, Zhong, Keebler, Jonathan, Han, Yujun, Levy, Shawn E., Boone, Braden E., Wimbish, Jack R., Waite, Lindsay L., Jones, Angela L., Carulli, John P., Day-Williams, Aaron G., Staropoli, John F., Xin, Winnie W., Chesi, Alessandra, Raphael, Alya R., McKenna-Yasek, Diane, Cady, Janet, de Jong, J. M. B. Vianney, Kenna, Kevin P., Smith, Bradley N., Topp, Simon, Miller, Jack, Gkazi, Athina, Al-Chalabi, Ammar, van den Berg, Leonard H., Veldink, Jan, Silani, Vincenzo, Ticozzi, Nicola, Shaw, Christopher E., Baloh, Robert H., Appel, Stanley, Simpson, Ericka, Lagier-Tourenne, Clotilde, Pulst, Stefan M., Gibson, Summer, Trojanowski, John Q., Elman, Lauren, McCluskey, Leo, Grossman, Murray, Shneider, Neil A., Chung, Wendy K., Ravits, John M., Glass, Jonathan D., Sims, Katherine B., Van Deerlin, Vivianna M., Maniatis, Tom, Hayes, Sebastian D., Ordureau, Alban, Swarup, Sharan, Landers, John, Baas, Frank, Allen, Andrew S., Bedlack, Richard S., Harper, J. Wade, Gitler, Aaron D., Rouleau, Guy A., Brown, Robert, Harms, Matthew B., Cooper, Gregory M., Harris, Tim, Myers, Richard M., and Goldstein, David B.

Published
2015

33. Variant‐to‐function mapping of late‐onset Alzheimer's disease GWAS loci in human microglial models implicates RTFDC1 as an effector gene at the CASS4 locus.

Author

Burton, Elizabeth A, Argenziano, Mariana, Cook, Kieona, Ridler, Molly, Su, Chun, Manduchi, Elisabetta, Hodge, Kenyaita M, Wang, Li‐San, Schellenberg, Gerard D., Pippin, James A., Wells, Andrew D., Anderson, Stewart A., Brown, Christopher D., Grant, Struan F.A., and Chesi, Alessandra

Abstract

Background: To date, Alzheimer's disease (AD) research has principally focused on neurons. In contrast, recent studies suggest that genetic mechanisms drive microglia towards prolonged inflammation in AD brains, exacerbating neurodegeneration. Indeed, many of the 70 disease‐associated loci uncovered with genome‐wide association studies (GWAS) reside near genes related to microglial function, such as TREM2. However, GWAS cannot directly identify causal variants or effector genes, as GWAS only reports the sentinel variant at a given locus, which tags all variants in high linkage disequilibrium. We used a combination of ATAC‐seq and high‐resolution promoter‐focused Capture‐C in two human microglial cell models to map interactions between GWAS‐implicated variants and their putative effector genes. We then validated an observed interaction between SNP rs6024870 at the 'CASS4' AD locus and the promoter of RTFDC1, a DNA damage response gene, using CRISPR‐Cas9. Method: We employed Capture‐C to characterize the genome‐wide interactions of all promoters in the HMC3 microglial cell line and iPSC‐derived microglia. We confirmed enhancer activity of the region harboring rs6024870 using dual‐luciferase assays. To validate the regulatory interaction with the Capture‐C implicated effector gene RTFDC1, we used lentiviral CRISPR‐Cas9 to delete an ∼400bp region containing the SNP in HMC3 cells. We confirmed changes in RNA and protein expression using RNA‐seq and immunoblotting. Furthermore, we assessed DNA damage repair deficiencies in enhancer knockout cells using an immunofluorescent assay for the histone mark GH2AX, and confirmed the role of RTFDC1 in the DNA damage phenotype using siRNA knockdown and lentiviral overexpression of RTFDC1, respectively. Result: Proxy SNP, rs6024870 (r2 = 0.93 to sentinel rs6014724), at the 'CASS4' locus, coincided with open chromatin and contacted the promoter of RTFDC1. Deletion of the putative enhancer region harboring rs6024870 by CRISPR‐Cas9 in HMC3 reduced the expression of both RTFDC1 mRNA and protein. Knockout cells had reduced ability to clear DNA double‐strand breaks (DSBs), and siRNA knockdown and lentiviral overexpression of RTFDC1 confirmed this phenotype was due to reduction of RTFDC1. Conclusion: We implicate rs6024870 and RTFDC1 as a SNP‐effector gene pair at the AD 'CASS4' GWAS locus, and the gene product is directly involved in driving a reduction in DNA DSB clearance. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

34. Variant‐gene pair in silico analyses and functional validation of LOAD GWAS loci in human brain‐relevant cell types identify EGFR as a target gene for potential drug repurposing.

Author

Leung, Yuk Yee, Kuksa, Pavel P., Cifello, Jeffrey, Greenfest‐Allen, Emily, Boateng, Louisa, Laub, Shannon, Tulina, Natalia, Schellenberg, Gerard D., Chesi, Alessandra, and Wang, Li‐San

Abstract

Background: Recent studies suggest genome‐wide‐association‐studies (GWAS) loci confer their effects on microglia in late‐onset Alzheimer's disease (LOAD) brains. Relatively fewer studies have investigated the effects of other genome‐wide significant loci (p<5e‐8) using human neurons. Method: GWAS itself cannot directly identify causal variant‐(effector)gene‐pairs as GWAS only reports the sentinel variant at a given locus. To map the physical interactions between GWAS‐implicated putative causal non‐coding variants and their corresponding effector genes in LOAD, we leveraged the post‐GWAS analytical framework, INFERNO, coupled with the largest harmonized functional genomics data catalog to date, FILER. Our goal was to unravel the effects of all 75 genome‐wide significant genetic loci reported in Bellenguez et al in human brain cell types. We searched for plausible evidence of causality for LOAD candidate variants in any brain‐specific variant‐gene pair through a total of 3,873 publicly curated datasets (123 enhancer, 3,153 epigenetics, 105 QTL) across 12 resources. We then validated the top variant‐gene pairs using high‐resolution promoter‐focused Capture C, ATAC‐seq and RNA‐seq datasets from several neuronal cell types and performed CRISPR interference. Result: The computational variant‐gene analyses identified a novel candidate causal SNP, rs74504435 (r2 = 0.94 to sentinel SNP rs76928645) at the SEC61G locus, located between SEC61G/EGFR. With a CADD score of 15, it is predicted as "regulatory" by both ENSEMBL and regulomeDB2. rs74504435 is found in ChromHMM and EpiMAP brain enhancers, and perturbs the transcriptional factor OCT6, which controls Schwann cell myelination. The minor allele T is protective to LOAD and downregulates EGFR in GTEx brain cortex (p = 2.3e‐13), CommonMind (FDR p = 5.8e‐5), and ROSMAP DLPFC (FDR p = 8.6e‐9) datasets with the same effect direction. In our Capture C and ATAC‐seq datasets, the SNP resides in open chromatin and directly contacts EGFR in human iPSC‐derived cortical neurons and ES‐derived hypothalamic neurons. We further validated a regulatory role for the enhancer region containing rs74504435 on EGFR using CRISPR interference in human microglial cells. Conclusion: Together, we identified a novel LOAD‐associated neuronal enhancer that drives EGFR gene expression. Further research is needed to investigate if EGFR inhibitors approved as anti‐cancer drugs can serve as potential candidates for repurposing as LOAD therapeutics. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

35. Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep

Author

Palermo, Justin, primary, Chesi, Alessandra, additional, Zimmerman, Amber, additional, Sonti, Shilpa, additional, Pahl, Matthew C., additional, Lasconi, Chiara, additional, Brown, Elizabeth B., additional, Pippin, James A., additional, Wells, Andrew D., additional, Doldur-Balli, Fusun, additional, Mazzotti, Diego R., additional, Pack, Allan I., additional, Gehrman, Phillip R., additional, Grant, Struan F.A., additional, and Keene, Alex C., additional

Published
2023
Full Text
View/download PDF

36. Intragenic loci within TOMM40 enhances APOE expression in human microglia

Author

Oron, Oded, primary, Ramirez, Aura Maria, additional, Wang, Liyong, additional, Vasquez, Marina Lipkin, additional, DeRosa, Brooke A, additional, Celis, Katrina, additional, Chesi, Alessandra, additional, Grant, Struan F.A., additional, Young, Juan J, additional, Nuytemans, Karen, additional, Vance, Jeffery M., additional, and Dykxhoorn, Derek M., additional

Published
2022
Full Text
View/download PDF

38. Zebrafish screen of high-confidence effector genes at insomnia GWAS loci implicates conserved regulators of sleep-wake behaviors

Author

Zimmerman, Amber J., primary, Doldur-Balli, Fusun, additional, Keenan, Brendan T., additional, Shetty, Zoe Y., additional, Palermo, Justin, additional, Chesi, Alessandra, additional, Sonti, Shilpa, additional, Pahl, Matthew C., additional, Brown, Elizabeth B., additional, Pippin, James A., additional, Wells, Andrew D., additional, Veatch, Olivia J., additional, Mazzotti, Diego R., additional, Krishnan, Anitra, additional, Gehrman, Phillip R., additional, Keene, Alex C., additional, Grant, Struan F.A., additional, and Pack, Allan I., additional

Published
2022
Full Text
View/download PDF

39. 298-OR: Variant-to-Gene Mapping at the Childhood Obesity Locus on chr12q13 and Subsequent Luciferase Assay Analyses Implicate rs71329as a Causal Variant within the 3’ UTR of FAIM2

Author

LITTLETON, SHERIDAN H., primary, BRADFIELD, JONATHAN, additional, PIPPIN, JAMES A., additional, SU, CHUN, additional, CHESI, ALESSANDRA, additional, WELLS, ANDREW D., additional, BERKOWITZ, ROBERT I., additional, PAHL, MATTHEW C., additional, and GRANT, STRUAN F., additional

Published
2022
Full Text
View/download PDF

40. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Author

Medina-Gomez, Carolina, Kemp, John P., Dimou, Niki L., Kreiner, Eskil, Chesi, Alessandra, Zemel, Babette S., Bønnelykke, Klaus, Boer, Cindy G., Ahluwalia, Tarunveer S., Bisgaard, Hans, Evangelou, Evangelos, Heppe, Denise H. M., Bonewald, Lynda F., Gorski, Jeffrey P., Ghanbari, Mohsen, Demissie, Serkalem, Duque, Gustavo, Maurano, Matthew T., Kiel, Douglas P., Hsu, Yi-Hsiang, C.J. van der Eerden, Bram, Ackert-Bicknell, Cheryl, Reppe, Sjur, Gautvik, Kaare M., Raastad, Truls, Karasik, David, van de Peppel, Jeroen, Jaddoe, Vincent W. V., Uitterlinden, André G., Tobias, Jonathan H., Grant, Struan F.A., Bagos, Pantelis G., Evans, David M., and Rivadeneira, Fernando

Published
2017
Full Text
View/download PDF

41. 0029 Developing a pipeline for translating genome-wide association signals to behavioral correlates of sleep dysfunction

Author

Zimmerman, Amber, primary, Palermo, Justin, additional, Chesi, Alessandra, additional, Sonti, Shilpa, additional, Lasconi, Chiara, additional, Brown, Elizabeth, additional, Pippin, James, additional, Wells, Andrew, additional, Doldur-Balli, Fusun, additional, Mazzotti, Diego, additional, Pack, Allan, additional, Gehrman, Philip, additional, Keene, Alex, additional, and Grant, Struan, additional

Published
2022
Full Text
View/download PDF

42. Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits

Author

Lasconi, Chiara, primary, Pahl, Matthew C, additional, Pippin, James A, additional, Su, Chun, additional, Johnson, Matthew E, additional, Chesi, Alessandra, additional, Boehm, Keith, additional, Manduchi, Elisabetta, additional, Ou, Kristy, additional, Golson, Maria L, additional, Wells, Andrew D, additional, Kaestner, Klaus H, additional, and Grant, Struan F A, additional

Published
2022
Full Text
View/download PDF

43. Additional file 8 of Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types

Author

Pahl, Matthew C., Le Coz, Carole, Su, Chun, Sharma, Prabhat, Thomas, Rajan M., Pippin, James A., Cruz Cabrera, Emylette, Johnson, Matthew E., Leonard, Michelle E., Lu, Sumei, Chesi, Alessandra, Sullivan, Kathleen E., Romberg, Neil, Grant, Struan F. A., and Wells, Andrew D.

Abstract

Additional file 8: Review history – Peer review history.

Published
2022
Full Text
View/download PDF

44. Additional file 1 of Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types

Author

Pahl, Matthew C., Le Coz, Carole, Su, Chun, Sharma, Prabhat, Thomas, Rajan M., Pippin, James A., Cruz Cabrera, Emylette, Johnson, Matthew E., Leonard, Michelle E., Lu, Sumei, Chesi, Alessandra, Sullivan, Kathleen E., Romberg, Neil, Grant, Struan F. A., and Wells, Andrew D.

Abstract

Additional file 1: Figures S1-S6 and Supplemental Table Legends. Figure S1. Summary of ATAC-seq datasets. Figure S2. Summary of Capture C datasets. Figure S3. Genomic Tracks indicating the position of SNPs of interest. Figure S4. Top IPA gene ontology network for genes implicated by COVID-19 V2G. Figure S5. The top IPA gene ontology network for transcription factors whose binding is predicted to be influenced by COVID-19-associated SNPs. Figure S6. Gating strategy for sorting of naïve B cells and GCB cells for this study.

Published
2022
Full Text
View/download PDF

45. Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets

Author

Nuytemans, Karen, primary, Lipkin Vasquez, Marina, additional, Wang, Liyong, additional, Van Booven, Derek, additional, Griswold, Antony J., additional, Rajabli, Farid, additional, Celis, Katrina, additional, Oron, Oded, additional, Hofmann, Natalia, additional, Rolati, Sophie, additional, Garcia‐Serje, Catherine, additional, Zhang, Shanshan, additional, Jin, Fulai, additional, Argenziano, Mariana, additional, Grant, Struan F.A., additional, Chesi, Alessandra, additional, Brown, Christopher D., additional, Young, Juan I., additional, Dykxhoorn, Derek M., additional, Pericak‐Vance, Margaret A., additional, and Vance, Jeffery M., additional

Published
2022
Full Text
View/download PDF

46. Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep

Author

Palermo, Justin, primary, Chesi, Alessandra, additional, Zimmerman, Amber, additional, Sonti, Shilpa, additional, Lasconi, Chiara, additional, Brown, Elizabeth B., additional, Pippin, James A., additional, Wells, Andrew D., additional, Doldur-Balli, Fusun, additional, Mazzotti, Diego R., additional, Pack, Allan I., additional, Gehrman, Phillip R., additional, Grant, Struan F.A., additional, and Keene, Alex C., additional

Published
2021
Full Text
View/download PDF

47. Ancestry‐specific intronic variants on the APOE ɛ4 haplotype influence enhancer activity and interaction with APOE promoter

Author

Nuytemans, Karen, primary, Vasquez, Marina Lipkin, additional, Rajabli, Farid, additional, Celis, Katrina, additional, Oron, Oded, additional, Van Booven, Derek, additional, Hofmann, Natalia K., additional, Argenziano, Mariana, additional, Chesi, Alessandra, additional, Grant, Struan F.A., additional, Brown, Christopher D., additional, Griswold, Anthony J., additional, Pericak‐Vance, Margaret A, additional, and Vance, Jeffery M., additional

Published
2021
Full Text
View/download PDF

48. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Author

Felix, Janine F., Bradfield, Jonathan P., Monnereau, Claire, van der Valk, Ralf J.P., Stergiakouli, Evie, Chesi, Alessandra, Gaillard, Romy, Feenstra, Bjarke, Thiering, Elisabeth, Kreiner-Møller, Eskil, Mahajan, Anubha, Pitkänen, Niina, Joro, Raimo, Cavadino, Alana, Huikari, Ville, Franks, Steve, Groen-Blokhuis, Maria M., Cousminer, Diana L., Marsh, Julie A., Lehtimäki, Terho, Curtin, John A., Vioque, Jesus, Ahluwalia, Tarunveer S., Myhre, Ronny, Price, Thomas S., Vilor-Tejedor, Natalia, Yengo, Loïc, Grarup, Niels, Ntalla, Ioanna, Ang, Wei, Atalay, Mustafa, Bisgaard, Hans, Blakemore, Alexandra I., Bonnefond, Amelie, Carstensen, Lisbeth, Eriksson, Johan, Flexeder, Claudia, Franke, Lude, Geller, Frank, Geserick, Mandy, Hartikainen, Anna-Liisa, Haworth, Claire M.A., Hirschhorn, Joel N., Hofman, Albert, Holm, Jens-Christian, Horikoshi, Momoko, Hottenga, Jouke Jan, Huang, Jinyan, Kadarmideen, Haja N., Kähönen, Mika, Kiess, Wieland, Lakka, Hanna-Maaria, Lakka, Timo A., Lewin, Alexandra M., Liang, Liming, Lyytikäinen, Leo-Pekka, Ma, Baoshan, Magnus, Per, McCormack, Shana E., McMahon, George, Mentch, Frank D., Middeldorp, Christel M., Murray, Clare S., Pahkala, Katja, Pers, Tune H., Pfäffle, Roland, Postma, Dirkje S., Power, Christine, Simpson, Angela, Sengpiel, Verena, Tiesler, Carla M. T., Torrent, Maties, Uitterlinden, André G., van Meurs, Joyce B., Vinding, Rebecca, Waage, Johannes, Wardle, Jane, Zeggini, Eleftheria, Zemel, Babette S., Dedoussis, George V., Pedersen, Oluf, Froguel, Philippe, Sunyer, Jordi, Plomin, Robert, Jacobsson, Bo, Hansen, Torben, Gonzalez, Juan R., Custovic, Adnan, Raitakari, Olli T., Pennell, Craig E., Widén, Elisabeth, Boomsma, Dorret I., Koppelman, Gerard H., Sebert, Sylvain, Järvelin, Marjo-Riitta, Hyppönen, Elina, McCarthy, Mark I., Lindi, Virpi, Harri, Niinikoski, Körner, Antje, Bønnelykke, Klaus, Heinrich, Joachim, Melbye, Mads, Rivadeneira, Fernando, Hakonarson, Hakon, Ring, Susan M., Smith, George Davey, Sørensen, Thorkild I.A., Timpson, Nicholas J., Grant, Struan F.A., Jaddoe, Vincent W.V., Kalkwarf, Heidi J., Lappe, Joan M., Gilsanz, Vicente, Oberfield, Sharon E., Shepherd, John A., Kelly, Andrea, and Zemel, Babette S.

Published
2016
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results