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1. Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms

Author

Yun Soo Hong, Sergiu Pasca, Wen Shi, Daniela Puiu, Nicole J. Lake, Monkol Lek, Meng Ru, Megan L. Grove, Anna Prizment, Corinne E. Joshu, Elizabeth A. Platz, Eliseo Guallar, Dan E. Arking, and Lukasz P. Gondek

Subjects
Science
Abstract

Abstract Clonal hematopoiesis of indeterminate potential is the primary pathogenic risk factor for myeloid neoplasms, while heteroplasmy (mutations in a subset of cellular mitochondrial DNA) is another marker of clonal expansion associated with hematological malignancies. We explore how these two markers relate and influence myeloid neoplasms incidence, and their role in risk stratification. We find that heteroplasmy is more common in individuals with clonal hematopoiesis of indeterminate potential, particularly those with higher variant allele fractions, multiple mutations, or spliceosome machinery mutations. Individuals with both markers have a higher risk of myeloid neoplasms than those with either alone. Furthermore, heteroplasmic variants with higher predicted deleteriousness increase the risk of myeloid neoplasms. Incorporating heteroplasmy in an existing risk score model for individuals with clonal hematopoiesis of indeterminate potential significantly improves sensitivity and better identifies high-risk groups. This suggests heteroplasmy as a clonal expansion marker and potentially as a biomarker for myeloid neoplasms development.

Published
2024
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2. Factors associated with blood mercury concentrations and their interactions with three glutathione S-transferase genes (GSTT1, GSTM1, and GSTP1): an exposure assessment study of typically developing Jamaican children

Author

Sheikh Farzana Zaman, Maureen Samms-Vaughan, Sepideh Saroukhani, Jan Bressler, Manouchehr Hessabi, Megan L. Grove, Sydonnie Shakespeare Pellington, Katherine A. Loveland, and Mohammad H. Rahbar

Subjects
Blood Hg concentrations, Glutathione S-transferase (GST) genes, Fish and seafood consumption, Interaction, Effect modifier, Jamaica, Pediatrics, RJ1-570
Abstract

Abstract Background Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms. Methods In this exposure assessment study we used data from 375 typically developing (TD) 2–8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general linear models (GLMs). Results We identified the child’s age, consumption of saltwater fish, canned fish (sardine, mackerel), string beans, grain, and starches (pasta, macaroni, noodles) as the environmental factors significantly associated with BHgCs (all P

Published
2024
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3. Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality

Author

Yun Soo Hong, Stephanie L. Battle, Wen Shi, Daniela Puiu, Vamsee Pillalamarri, Jiaqi Xie, Nathan Pankratz, Nicole J. Lake, Monkol Lek, Jerome I. Rotter, Stephen S. Rich, Charles Kooperberg, Alex P. Reiner, Paul L. Auer, Nancy Heard-Costa, Chunyu Liu, Meng Lai, Joanne M. Murabito, Daniel Levy, Megan L. Grove, Alvaro Alonso, Richard Gibbs, Shannon Dugan-Perez, Lukasz P. Gondek, Eliseo Guallar, and Dan E. Arking

Subjects
Science
Abstract

Abstract Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.

Published
2023
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4. Association Between Whole Blood–Derived Mitochondrial DNA Copy Number, Low‐Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk

Author

Xue Liu, Xianbang Sun, Yuankai Zhang, Wenqing Jiang, Meng Lai, Kerri L. Wiggins, Laura M. Raffield, Lawrence F. Bielak, Wei Zhao, Achilleas Pitsillides, Jeffrey Haessler, Yinan Zheng, Thomas W. Blackwell, Jie Yao, Xiuqing Guo, Yong Qian, Bharat Thyagarajan, Nathan Pankratz, Stephen S. Rich, Kent D. Taylor, Patricia A. Peyser, Susan R. Heckbert, Sudha Seshadri, Eric Boerwinkle, Megan L. Grove, Nicholas B. Larson, Jennifer A. Smith, Ramachandran S. Vasan, Annette L. Fitzpatrick, Myriam Fornage, Jun Ding, April P. Carson, Goncalo Abecasis, Josée Dupuis, Alexander Reiner, Charles Kooperberg, Lifang Hou, Bruce M. Psaty, James G. Wilson, Daniel Levy, Jerome I. Rotter, Joshua C. Bis, Claudia L. Satizabal, Dan E. Arking, and Chunyu Liu

Subjects
cardiometabolic risk factors, cardiovascular disease, low‐density lipoprotein cholesterol, Mendelian randomization, mitochondrial DNA copy number, vascular atherosclerosis, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P

Published
2023
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5. Longitudinal change in blood DNA epigenetic signature after smoking cessation

Author

Amena Keshawarz, Roby Joehanes, Weihua Guan, Tianxiao Huan, Dawn L. DeMeo, Megan L. Grove, Myriam Fornage, Daniel Levy, and George O’Connor

Subjects
cigarette smoking, dna methylation, epigenetics, longitudinal analysis, Genetics, QH426-470
Abstract

Cigarette smoking is associated with epigenetic changes that may be reversible following smoking cessation. Whole blood DNA methylation was evaluated in Framingham Heart Study Offspring (n = 169) and Third Generation (n = 30) cohort participants at two study visits 6 years apart and in Atherosclerosis Risk in Communities (ARIC) study (n = 222) participants at two study visits 20 years apart. Changes in DNA methylation (delta β values) at 483,565 cytosine-phosphate-guanine (CpG) sites and differentially methylated regions (DMRs) were compared between participants who were current, former, or never smokers at both visits (current-current, former-former, never-never, respectively), versus those who quit in the interim (current-former). Interim quitters had more hypermethylation at four CpGs annotated to AHRR, one CpG annotated to F2RL3, and one intergenic CpG (cg21566642) compared with current-current smokers (FDR < 0.02 for all), and two significant DMRs were identified. While there were no significant differentially methylated CpGs in the comparison of interim quitters and former-former smokers, 106 DMRs overlapping with small nucleolar RNA were identified. As compared with all non-smokers, current-current smokers additionally had more hypermethylation at two CpG sites annotated to HIVEP3 and TMEM126A, respectively, and another intergenic CpG (cg14339116). Gene transcripts associated with smoking cessation were implicated in immune responses, cell homoeostasis, and apoptosis. Smoking cessation is associated with early reversion of blood DNA methylation changes at CpG sites annotated to AHRR and F2RL3 towards those of never smokers. Associated gene expression suggests a role of longitudinal smoking-related DNA methylation changes in immune response processes.

Published
2022
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6. Association of low-frequency and rare coding variants with information processing speed

Author

Jan Bressler, Gail Davies, Albert V. Smith, Yasaman Saba, Joshua C. Bis, Xueqiu Jian, Caroline Hayward, Lisa Yanek, Jennifer A. Smith, Saira S. Mirza, Ruiqi Wang, Hieab H. H. Adams, Diane Becker, Eric Boerwinkle, Archie Campbell, Simon R. Cox, Gudny Eiriksdottir, Chloe Fawns-Ritchie, Rebecca F. Gottesman, Megan L. Grove, Xiuqing Guo, Edith Hofer, Sharon L. R. Kardia, Maria J. Knol, Marisa Koini, Oscar L. Lopez, Riccardo E. Marioni, Paul Nyquist, Alison Pattie, Ozren Polasek, David J. Porteous, Igor Rudan, Claudia L. Satizabal, Helena Schmidt, Reinhold Schmidt, Stephen Sidney, Jeannette Simino, Blair H. Smith, Stephen T. Turner, Sven J. van der Lee, Erin B. Ware, Rachel A. Whitmer, Kristine Yaffe, Qiong Yang, Wei Zhao, Vilmundur Gudnason, Lenore J. Launer, Annette L. Fitzpatrick, Bruce M. Psaty, Myriam Fornage, M. Arfan Ikram, Cornelia M. van Duijn, Sudha Seshadri, Thomas H. Mosley, and Ian J. Deary

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

Published
2021
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7. Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Author

Adrienne Tin, Pascal Schlosser, Pamela R. Matias-Garcia, Chris H. L. Thio, Roby Joehanes, Hongbo Liu, Zhi Yu, Antoine Weihs, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L. Min, Victoria L. Halperin Kuhns, Adebowale A. Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A. Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Jan Bressler, Monique M. B. Breteler, Cristian Carmeli, Layal Chaker, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R. Cox, Graciela E. Delgado, Kai-Uwe Eckardt, Arif B. Ekici, Karlhans Endlich, James S. Floyd, Eliza Fraszczyk, Xu Gao, Xīn Gào, Allan C. Gelber, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L. Grove, Sarah E. Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A. Hurme, Shih-Jen Hwang, Sharon L. R. Kardia, Silva Kasela, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Florian Kronenberg, Brigitte Kühnel, Christine Ladd-Acosta, Terho Lehtimäki, Lars Lind, Dan Liu, Donald M. Lloyd-Jones, Stefan Lorkowski, Ake T. Lu, Riccardo E. Marioni, Winfried März, Daniel L. McCartney, Karlijn A. C. Meeks, Lili Milani, Pashupati P. Mishra, Matthias Nauck, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Scott M. Ratliff, Alex P. Reiner, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A. Smith, Nona Sotoodehnia, Hannah R. Stocker, Silvia Stringhini, Johan Sundström, Brenton R. Swenson, Joyce B. J. van Meurs, Jana V. van Vliet-Ostaptchouk, Andrea Venema, Uwe Völker, Juliane Winkelmann, Bruce H. R. Wolffenbuttel, Wei Zhao, Yinan Zheng, The Estonian Biobank Research Team, The Genetics of DNA Methylation Consortium, Marie Loh, Harold Snieder, Melanie Waldenberger, Daniel Levy, Shreeram Akilesh, Owen M. Woodward, Katalin Susztak, Alexander Teumer, and Anna Köttgen

Subjects
Science
Abstract

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.

Published
2021
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8. Meta-analyses identify DNA methylation associated with kidney function and damage

Author

Pascal Schlosser, Adrienne Tin, Pamela R. Matias-Garcia, Chris H. L. Thio, Roby Joehanes, Hongbo Liu, Antoine Weihs, Zhi Yu, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L. Min, Adebowale A. Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A. Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Monique M. B. Breteler, Cristian Carmeli, Layal Chaker, John C. Chambers, Shelley A. Cole, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R. Cox, Niek de Klein, Graciela E. Delgado, Arce Domingo-Relloso, Kai-Uwe Eckardt, Arif B. Ekici, Karlhans Endlich, Kathryn L. Evans, James S. Floyd, Myriam Fornage, Lude Franke, Eliza Fraszczyk, Xu Gao, Xīn Gào, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L. Grove, Sarah E. Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A. Hurme, Shih-Jen Hwang, Marjo-Riitta Jarvelin, Sharon L. R. Kardia, Silva Kasela, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Holly Kramer, Florian Kronenberg, Brigitte Kühnel, Terho Lehtimäki, Lars Lind, Dan Liu, Yongmei Liu, Donald M. Lloyd-Jones, Kurt Lohman, Stefan Lorkowski, Ake T. Lu, Riccardo E. Marioni, Winfried März, Daniel L. McCartney, Karlijn A. C. Meeks, Lili Milani, Pashupati P. Mishra, Matthias Nauck, Ana Navas-Acien, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Scott M. Ratliff, Alex P. Reiner, Sylvia E. Rosas, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A. Smith, Nona Sotoodehnia, Hannah R. Stocker, Silvia Stringhini, Johan Sundström, Brenton R. Swenson, Maria Tellez-Plaza, Joyce B. J. van Meurs, Jana V. van Vliet-Ostaptchouk, Andrea Venema, Niek Verweij, Rosie M. Walker, Matthias Wielscher, Juliane Winkelmann, Bruce H. R. Wolffenbuttel, Wei Zhao, Yinan Zheng, Estonian Biobank Research Team, Genetics of DNA Methylation Consortium, Marie Loh, Harold Snieder, Daniel Levy, Melanie Waldenberger, Katalin Susztak, Anna Köttgen, and Alexander Teumer

Subjects
Science
Abstract

Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.

Published
2021
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9. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Author

Garan Jones, Katerina Trajanoska, Adam J. Santanasto, Najada Stringa, Chia-Ling Kuo, Janice L. Atkins, Joshua R. Lewis, ThuyVy Duong, Shengjun Hong, Mary L. Biggs, Jian’an Luan, Chloe Sarnowski, Kathryn L. Lunetta, Toshiko Tanaka, Mary K. Wojczynski, Ryan Cvejkus, Maria Nethander, Sahar Ghasemi, Jingyun Yang, M. Carola Zillikens, Stefan Walter, Kamil Sicinski, Erika Kague, Cheryl L. Ackert-Bicknell, Dan E. Arking, B. Gwen Windham, Eric Boerwinkle, Megan L. Grove, Misa Graff, Dominik Spira, Ilja Demuth, Nathalie van der Velde, Lisette C. P. G. M. de Groot, Bruce M. Psaty, Michelle C. Odden, Alison E. Fohner, Claudia Langenberg, Nicholas J. Wareham, Stefania Bandinelli, Natasja M. van Schoor, Martijn Huisman, Qihua Tan, Joseph Zmuda, Dan Mellström, Magnus Karlsson, David A. Bennett, Aron S. Buchman, Philip L. De Jager, Andre G. Uitterlinden, Uwe Völker, Thomas Kocher, Alexander Teumer, Leocadio Rodriguéz-Mañas, Francisco J. García, José A. Carnicero, Pamela Herd, Lars Bertram, Claes Ohlsson, Joanne M. Murabito, David Melzer, George A. Kuchel, Luigi Ferrucci, David Karasik, Fernando Rivadeneira, Douglas P. Kiel, and Luke C. Pilling

Subjects
Science
Abstract

Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.

Published
2021
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10. Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

Author

Christina A. Castellani, Ryan J. Longchamps, Jason A. Sumpter, Charles E. Newcomb, John A. Lane, Megan L. Grove, Jan Bressler, Jennifer A. Brody, James S. Floyd, Traci M. Bartz, Kent D. Taylor, Penglong Wang, Adrienne Tin, Josef Coresh, James S. Pankow, Myriam Fornage, Eliseo Guallar, Brian O’Rourke, Nathan Pankratz, Chunyu Liu, Daniel Levy, Nona Sotoodehnia, Eric Boerwinkle, and Dan E. Arking

Subjects
Epigenomics, Mitochondrial DNA, Cardiovascular disease, Mortality, Medicine, Genetics, QH426-470
Abstract

Abstract Background Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. Methods To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Results Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P

Published
2020
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11. Association of mitochondrial DNA copy number with cardiometabolic diseases

Author

Xue Liu, Ryan J. Longchamps, Kerri L. Wiggins, Laura M. Raffield, Lawrence F. Bielak, Wei Zhao, Achilleas Pitsillides, Thomas W. Blackwell, Jie Yao, Xiuqing Guo, Nuzulul Kurniansyah, Bharat Thyagarajan, Nathan Pankratz, Stephen S. Rich, Kent D. Taylor, Patricia A. Peyser, Susan R. Heckbert, Sudha Seshadri, L. Adrienne Cupples, Eric Boerwinkle, Megan L. Grove, Nicholas B. Larson, Jennifer A. Smith, Ramachandran S. Vasan, Tamar Sofer, Annette L. Fitzpatrick, Myriam Fornage, Jun Ding, Adolfo Correa, Goncalo Abecasis, Bruce M. Psaty, James G. Wilson, Daniel Levy, Jerome I. Rotter, Joshua C. Bis, Claudia L. Satizabal, Dan E. Arking, and Chunyu Liu

Subjects
mitochondrial DNA copy number, cardiometabolic disease, whole-genome sequencing, whole-exom sequencing, aging, white blood cell counts, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10−13) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10−238), hypertension (p = 2.8 × 10−50), diabetes (p = 3.6 × 10−7), and hyperlipidemia (p = 6.3 × 10−56). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

Published
2021
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12. Corrigendum to ‘Association of sickle cell trait with measures of cognitive function and dementia in African Americans’ eNeurologicalSci, Vol. 16 (2019), 100,201

Author

Nemin Chen, Christina Caruso, Alvaro Alonso, Vimal K. Derebail, Abhijit V. Kshirsagar, A. Richey Sharrett, Nigel S. Key, Rebecca F. Gottesman, Megan L. Grove, Jan Bressler, Eric Boerwinkle, B. Gwen Windham, Thomas H. Mosley, Jr, and Hyacinth I. Hyacinth

Subjects
Neurology. Diseases of the nervous system, RC346-429
Published
2020
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13. Correction: Association of low-frequency and rare coding variants with information processing speed

Author

Jan Bressler, Gail Davies, Albert V. Smith, Yasaman Saba, Joshua C. Bis, Xueqiu Jian, Caroline Hayward, Lisa Yanek, Jennifer A. Smith, Saira S. Mirza, Ruiqi Wang, Hieab H. H. Adams, Diane Becker, Eric Boerwinkle, Archie Campbell, Simon R. Cox, Gudny Eiriksdottir, Chloe Fawns-Ritchie, Rebecca F. Gottesman, Megan L. Grove, Xiuqing Guo, Edith Hofer, Sharon L. R. Kardia, Maria J. Knol, Marisa Koini, Oscar L. Lopez, Riccardo E. Marioni, Paul Nyquist, Alison Pattie, Ozren Polasek, David J. Porteous, Igor Rudan, Claudia L. Satizabal, Helena Schmidt, Reinhold Schmidt, Stephen Sidney, Jeannette Simino, Blair H. Smith, Stephen T. Turner, Sven J. van der Lee, Erin B. Ware, Rachel A. Whitmer, Kristine Yaffe, Qiong Yang, Wei Zhao, Vilmundur Gudnason, Lenore J. Launer, Annette L. Fitzpatrick, Bruce M. Psaty, Myriam Fornage, M. Arfan Ikram, Cornelia M. van Duijn, Sudha Seshadri, Thomas H. Mosley, and Ian J. Deary

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published
2022
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14. Association of sickle cell trait with measures of cognitive function and dementia in African Americans

Author

Nemin Chen, Christina Caruso, Alvaro Alonso, Vimal K. Derebail, Abhijit V. Kshirsagar, A. Richey Sharrett, Nigel S. Key, Rebecca F. Gottesman, Megan L. Grove, Jan Bressler, Eric Boerwinkle, B. Gwen Windham, Thomas H. Mosley, Jr, and Hyacinth I. Hyacinth

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Objective: The incidence and prevalence of cognitive decline and dementia are significantly higher among African Americans compared with non-Hispanic Whites. The aim of this study was to determine whether inheritance of the sickle cell trait (SCT) i.e. heterozygosity for the sickle cell mutation increases the risk of cognitive decline or dementia Among African Americans. Methods: We studied African American participants enrolled in the Atherosclerosis Risk in Communities study. SCT genotype at baseline and outcome data from cognitive assessments at visits 2, 4 and 5, and an MRI performed at visit 5 were analyzed for the association between SCT and risk of cognitive impairment and/or dementia. Results: There was no significant difference in risk factors profile between participants with SCT (N = 176) and those without SCT (N = 2532). SCT was not independently associated with a higher prevalence of global or domain-specific cognitive impairment at baseline or with more rapid cognitive decline. Participants with SCT had slightly lower incidence of dementia (HR = 0.63 [0.38, 1.05]). On the other hand, SCT seems to interact with the apolipoprotein E ε4 risk allele resulting in poor performance on digit symbol substitution test at baseline (z-score = −0.08, Pinteraction = 0.05) and over time (z-score = −0.12, Pinteraction = 0.04); and with diabetes mellitus leading to a moderately increased risk of dementia (HR = 2.06 [0.89, 4.78], Pinteraction = 0.01). Conclusions: SCT was not an independent risk factor for prevalence or incidence of cognitive decline or dementia, although it may interact with and modify other putative risk factors for cognitive decline and dementia. Keywords: Sickle cell trait, Health disparity, Cognitive impairment, Genetic epidemiology, Cerebrovascular disease

Published
2019
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15. Additive or Interactive Associations of Food Allergies with Glutathione S-Transferase Genes in Relation to ASD and ASD Severity in Jamaican Children

Author

Sepideh Saroukhani, Maureen Samms-Vaughan, Jan Bressler, MinJae Lee, Courtney Byrd-Williams, Manouchehr Hessabi, Megan L. Grove, Sydonnie Shakespeare-Pellington, Katherine A. Loveland, and Mohammad H. Rahbar

Abstract

To investigate additive and interactive associations of food allergies with three glutathione S-transferase (GST) genes in relation to ASD and ASD severity in Jamaican children. Using data from 344 1:1 age- and sex-matched ASD cases and typically developing controls, we assessed additive and interactive associations of food allergies with polymorphisms in GST genes (GSTM1, GSTP1 and GSTT1) in relation to ASD by applying conditional logistic regression models, and in relation to ASD severity in ASD cases as measured by the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) total and domains specific comparison scores (CSs) by fitting general linear models. Although food allergies and GST genes were not associated with ASD, ASD cases allergic to non-dairy food had higher mean ADOS-2 Restricted and Repetitive Behaviors (RRB) CS (8.8 vs. 8.0, P = 0.04). In addition, allergy to dairy was associated with higher mean RRB CS only among ASD cases with GSTT1 DD genotype (9.9 vs. 7.8, P < 0.01, interaction P = 0.01), and GSTP1 Val/Val genotype under a recessive genetic model (9.8 vs. 7.8, P = 0.02, interaction P = 0.06). Our findings are consistent with the role for GST genes in ASD and food allergies, though require replication in other populations.

Published
2024
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16. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 3; referees: 2 approved]

Author

Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London

Subjects
Genomics, Medicine, Science
Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018
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17. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 2; referees: 2 approved]

Author

Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London

Subjects
Genomics, Medicine, Science
Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018
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18. A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease

Author

Josée Dupuis, Victoria E. Jackson, Hanfei Xu, Brian D. Hobbs, Edwin K. Silverman, Michael H. Cho, Megan L. Grove, Jennifer N. Nguyen, Jiangyuan Liu, George T. O'Connor, Natalie Terzikhan, Ani Manichaikul, Patricia A. Cassano, Colleen M. Sitlani, Buhm Han, Ian P. Hall, Bing Yu, Sina A. Gharib, Lies Lahousse, Louise V. Wain, Traci M. Bartz, Christopher J. Benway, R. Graham Barr, Phuwanat Sakornsakolpat, Guy Brusselle, Stephanie J. London, Kun Hee Kim, Martin D. Tobin, Matthew Moll, Jinkyeong Park, Woo Jin Kim, Bonnie K Patchen, Stephen S. Rich, and Epidemiology

Subjects
0301 basic medicine, Nonsynonymous substitution, Pulmonary and Respiratory Medicine, EXPRESSION, Genetic Markers, Physiology, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, chronic obstructive pulmonary disease, GENETIC ASSOCIATION, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, DESIGN, Meta-Analysis as Topic, Physiology (medical), Medicine and Health Sciences, genomics, COPD, Humans, Exome, Genetic Predisposition to Disease, exon, Allele, GENOME-WIDE ASSOCIATION, Genotyping, Genetic association, Genetics, ZINC-FINGER PROTEIN, Odds ratio, Cell Biology, GENOTYPE, Minor allele frequency, LUNG-FUNCTION, functional, 030104 developmental biology, 030228 respiratory system, ATHEROSCLEROSIS, Gene Expression Regulation, SMOKING, exome, Genome-Wide Association Study, Research Article
Abstract

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( P < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B ( GSDMB) splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, P = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 ( CCHCR1), a gene involved in regulating cell proliferation, were associated with COPD (both P < 0.0001). The SERPINA1 Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17–1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.

Published
2021
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19. Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

Author

Ryan J. Longchamps, Rozenn N. Lemaitre, Traci M. Bartz, Henning Tiemeier, Anna L. Guyatt, Nir Barzilai, A.G. Uitterlinden, A. C. Y. Mak, C M van Duijn, Eric Boerwinkle, Mary F. Feitosa, Stephen S. Rich, Rui Xia, Gil Atzmon, Santiago Rodriguez, Bruce M. Psaty, Dan E. Arking, Chloé Sarnowski, Jerome I. Rotter, Mark O. Goodarzi, Megan L. Grove, Jennifer A. Brody, Joanne M. Murabito, J.B. van Meurs, Mary K. Wojczynski, K. Ye, Aviv Bergman, Nona Sotoodehnia, Tom R. Gaunt, Le Yu, Nathan Pankratz, Myriam Fornage, Najaf Amin, Tim Kacprowski, Kathryn L. Lunetta, Ching-Ti Liu, Jingyun Yang, Kent D. Taylor, Fernando Rivadeneira, David A. Bennett, Kimberley Burrows, S. Y. Yang, Michael A. Province, Wei Shi, C. M. Sitlani, Laura M. Raffield, P. L. De Jager, Leslie A. Lange, Aldi T. Kraja, Linda Broer, John Lane, Christina A. Castellani, Epidemiology, and Internal Medicine

Subjects
Male, Mitochondrial DNA, Aging, DNA Copy Number Variations, 1.1 Normal biological development and functioning, Single-nucleotide polymorphism, Genome-wide association study, Biology, Cardiovascular, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Paediatrics and Reproductive Medicine, Complementary and Alternative Medicine, SDG 3 - Good Health and Well-being, Underpinning research, Genetics, Humans, Genetic Predisposition to Disease, Platelet activation, Polymorphism, Gene, Genetics (clinical), Original Investigation, Cell Proliferation, Aged, Cancer, Genetics & Heredity, Nucleotides, Human Genome, DNA, Single Nucleotide, Middle Aged, Platelet Activation, Phenotype, Human genetics, Mitochondria, Mitochondrial, Female, Liver function, Generic health relevance, Megakaryocytes, Genome-Wide Association Study
Abstract

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10–15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10–8) and mtDNA replication (p = 1.2 × 10–7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10–4).

Published
2022
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20. Additive and Interactive Associations of Environmental and Sociodemographic Factors with the Genotypes of Three Glutathione S-Transferase Genes in Relation to the Blood Arsenic Concentrations of Children in Jamaica

Author

Mohammad H. Rahbar, Maureen Samms-Vaughan, Yuansong Zhao, Sepideh Saroukhani, Sheikh F. Zaman, Jan Bressler, Manouchehr Hessabi, Megan L. Grove, Sydonnie Shakspeare-Pellington, and Katherine A. Loveland

Subjects
Jamaica, Polymorphism, Genetic, Sociodemographic Factors, Genotype, glutathione S-transferase (GST) genes, Health, Toxicology and Mutagenesis, Public Health, Environmental and Occupational Health, interaction, Article, Arsenic, Glutathione S-Transferase pi, children, Risk Factors, Case-Control Studies, food consumption, Humans, Medicine, Genetic Predisposition to Disease, blood arsenic concentrations, Child, Glutathione Transferase
Abstract

Arsenic (As) is a metalloid that has been classified as a xenobiotic with toxic effects on human beings, especially on children. Since the soil in Jamaica contains As, dietary intake is considered the main source of As exposure in Jamaicans. In addition, glutathione S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play an important role in the metabolism of xenobiotics including As in humans. Using data from 375 typically developing children (2–8 years) in Jamaica, we investigated the environmental and sociodemographic factors, as well as their possible interactions with the children’s genotype for GST genes in relation to having a detectable level of blood As concentration (i.e., >1.3 μg/L). Using multivariable logistic regression, we have identified environmental factors significantly associated with blood As concentrations that include a child’s age, parental education levels, and the consumption of saltwater fish, cabbage, broad beans, and avocado (all p < 0.01). Based on the multivariable analysis including gene x environment interactions, we found that among children with the Ile/Ile genotype for GSTP1 Ile105Val, children who consumed avocado had higher odds of having a detectable blood As concentration compared to children who did not eat avocado.

Published
2022
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21. A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Author

Rui Xia, Jordana T. Bell, Roby Joehanes, Abbas Dehghan, Sharon L.R. Kardia, Erin B. Ware, Deugi Zhi, Devin Absher, Annette Peters, Martina Müller-Nurasyid, Daniel Levy, Nona Sotoodehnia, Wei Chen, Coleen M. Damcott, Lifang Hou, Donna K. Arnett, Weihua Guan, Jincheng Shen, Steve Horvath, Rory P. Wilson, Kim Valeska Emilie Braun, Lars Lind, Wei Zhao, Myriam Fornage, Shengxu Li, Mina A. Jhun, Paula Singmann, Elena Carnero-Montoro, Michael M. Mendelson, Jennifer A. Smith, Xiaoping Zhao, Marguerite R. Irvin, Bruce M. Psaty, Andrea A. Baccarelli, Jeffrey R. O'Connell, Mohammad Arfan Ikram, Traci M. Bartz, Erik Ingelsson, Klodian Dhana, Melanie Waldenberger, Stefan Gustafsson, Yii-Der Ida Chen, Thomas Meitinger, Themistocles L. Assimes, Elias Salfati, Tao Zhang, Pfeiffer Liliane, Dianjianyi Sun, Rahul Gondalia, Eric Boerwinkle, Philip S. Tsao, Christian Gieger, Eric A. Whitsel, Chen Yao, Tim D. Spector, Alan R. Shuldiner, Åsa K. Hedman, Joyce B. J. van Meurs, May E. Montasser, Anh N. Do, Mohsen Ghanbari, André G. Uitterlinden, Megan L. Grove, Jennifer A. Brody, Epidemiology, and Internal Medicine

Subjects
Adult, Epigenomics, Male, 0301 basic medicine, Science, Concordance, Quantitative Trait Loci, Ethnic group, General Physics and Astronomy, Blood lipids, 030204 cardiovascular system & hematology, Biology, Article, White People, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, Epigenome, 03 medical and health sciences, 0302 clinical medicine, Genetics, Leukocytes, Humans, Dyslipidaemias, Aged, Medicinsk genetik, Genetic association, Multidisciplinary, Carnitine O-Palmitoyltransferase, Hispanic or Latino, General Chemistry, DNA Methylation, Middle Aged, Lipids, Black or African American, 030104 developmental biology, Meta-analysis, DNA methylation, Epigenetics, CpG Islands, Female, Lipoproteins, HDL, Medical Genetics
Abstract

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups., Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.

Published
2021

22. Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies

Author

Clary B. Clish, Tao Wang, Jordi Merino, Robert E. Gerszten, Bianca Porneala, David L. Perkins, Miguel Ruiz-Canela, Qibin Qi, Wenshuang Wang, Jordi Salas-Salvadó, Josée Dupuis, Casey M. Rebholz, Mykhaylo Usyk, Jie Hu, Jin C. Chai, Frank B. Hu, Martha L. Daviglus, Miguel Ángel Martínez-González, Guo Chong Chen, Zheng Wang, Wei Bao, Bing Yu, JoAnn E. Manson, Jee-Young Moon, Jun Li, James B. Meigs, Kathryn M. Rexrode, Robert D. Burk, Bharat Thyagarajan, Rob Knight, Jianwen Cai, Elizabeth Selvin, Megan L. Grove, Robert C. Kaplan, Eric Boerwinkle, Ngoc Quynh H. Nguyen, Elena V. Feofanova, and Thomas J. Wang

Subjects
0301 basic medicine, medicine.medical_treatment, Clinical Sciences, 030209 endocrinology & metabolism, Gut flora, Kynurenate, Oral and gastrointestinal, Article, Paediatrics and Reproductive Medicine, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes Mellitus, Genetics, medicine, 2.2 Factors relating to the physical environment, Humans, Obesity, Aetiology, Metabolic and endocrine, Kynurenine, Nutrition, Bifidobacterium, Lactase, Gastroenterology & Hepatology, biology, Bacteria, Prevention, Human Genome, Diabetes, Gastroenterology, Tryptophan, biology.organism_classification, Quinolinate, Diet, Gastrointestinal Microbiome, Lactase persistence, 030104 developmental biology, chemistry, Diabetes Mellitus, Type 2, dietary factors, Type 2
Abstract

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.MethodWe analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.ResultsTryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-usingFirmicutes. We identified a novel association between a host functionalLCTvariant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gutBifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gutBifidobacteriumand serum indolepropionate only among genetically lactase non-persistent individuals.ConclusionHigher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host–microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Published
2021

23. Interaction of Blood Manganese Concentrations with GSTT1 in Relation to Autism Spectrum Disorder in Jamaican Children

Author

Megan L. Grove, MinJae Lee, Sepideh Saroukhani, Jan Bressler, Sydonnie Shakespeare-Pellington, Katherine A. Loveland, Maureen Samms-Vaughan, Manouchehr Hessabi, Jing Zhang, and Mohammad H. Rahbar

Subjects
Male, medicine.medical_specialty, Genotype, Autism Spectrum Disorder, Article, 03 medical and health sciences, Typically developing, GSTP1, 0302 clinical medicine, Internal medicine, Genetic model, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Genetic Predisposition to Disease, Child, Glutathione Transferase, Manganese, Polymorphism, Genetic, 05 social sciences, medicine.disease, Black or African American, Endocrinology, Glutathione S-Transferase pi, Autism spectrum disorder, Case-Control Studies, Child, Preschool, Autism, Dominant model, Conditional logistic regression, Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

Using data from 266 age- and sex-matched pairs of Jamaican children with autism spectrum disorder (ASD) and typically developing (TD) controls (2–8 years), we investigated whether glutathione S-transferase theta 1 (GSTT1) modifies the association between blood manganese concentrations (BMC) and ASD. After adjusting conditional logistic regression models for socioeconomic status and the interaction between GSTT1 and GSTP1 (glutathione S-transferase pi 1), using a recessive genetic model for GSTT1 and either a co-dominant or dominant model for GSTP1, the interaction between GSTT1 and BMC was significant (P = 0.02, P = 0.01, respectively). Compared to controls, ASD cases with GSTT1-DD genotype had 4.33 and 4.34 times higher odds of BMC > 12 vs. ≤ 8.3 μg/L, respectively. Replication in other populations is warranted.

Published
2021

24. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author

Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center

Subjects
Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

Published
2019
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25. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality

Author

A. Mark Richards, W.H. Wilson Tang, Julie A. Johnson, Stanley L. Hazen, Danilo Fliser, Heribert Schunkert, Yan Gong, Andreas Martinsson, Peter Lipp, Yi-An Ko, Stephen Zewinger, Andrej Teren, Marcus E. Kleber, Ian Ford, Sarah Triem, David J. Stott, Matthias C. Reichert, Hannah Campbell, Dawn M. Waterworth, Ulrich Laufs, Caitrin W. McDonough, Stefan Wagenpfeil, Marcin Krawczyk, Michael Böhm, J. Wouter Jukema, Naveed Sattar, Shichao Pang, Markus Scholz, Rafael Kramann, Stella Trompet, Philipp Ege, Niclas Eriksson, David Schmit, Christie M. Ballantyne, Claes Held, Marie-Pierre Dubé, Winfried März, Thimoteus Speer, Jörn Walter, Stefan James, Maxine Sun, Hooman Allayee, Lars Wallentin, Harvey D. White, Vicky A. Cameron, Stefan J Schunk, Sharon Cresci, Barbara A. Niemeyer, Susanne N. Weber, Anna P. Pilbrow, Emmanuel Ampofo, J. Gustav Smith, Sascha Tierling, Jean-Claude Tardif, Robert N. Doughty, Rhonda M. Cooper-DeHoff, Arshed A. Quyyumi, Ralph Burkhardt, John A. Spertus, Chang Liu, Eric Boerwinkle, Wolfgang Koenig, Tamim Sarakpi, Yassamin Feroz-Zada, Jaana Hartiala, Isabella Jaumann, Vinicius Tragante, and Megan L. Grove

Subjects
Inflammasomes, Inflammation, 030204 cardiovascular system & hematology, Systemic inflammation, Coronary artery disease, Inflammasome, 03 medical and health sciences, 0302 clinical medicine, NLRP3, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Humans, Cardiac and Cardiovascular Systems, Serum amyloid A, Allele, 030304 developmental biology, 0303 health sciences, Kardiologi, biology, integumentary system, business.industry, C-reactive protein, R1, 3. Good health, Minor allele frequency, Cardiovascular diseases, Immunology, biology.protein, Leukocytes, Mononuclear, Apolipoprotein C3, medicine.symptom, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Published
2021

26. Associations of Metabolic Genes (GSTT1, GSTP1, GSTM1) and Blood Mercury Concentrations Differ in Jamaican Children with and without Autism Spectrum Disorder

Author

Compton Beecher, Manouchehr Hessabi, Wayne McLaughlin, Megan L. Grove, Sepideh Saroukhani, Sydonnie Shakspeare-Pellington, Jan Bressler, Mohammad H. Rahbar, Maureen Samms-Vaughan, and Katherine A. Loveland

Subjects
medicine.medical_specialty, Jamaica, Health, Toxicology and Mutagenesis, glutathione S-transferase (GST) genes, lcsh:Medicine, interaction, 010501 environmental sciences, Biology, urologic and male genital diseases, 01 natural sciences, 03 medical and health sciences, GSTP1, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, Genetic model, Genotype, medicine, Gene, neoplasms, 0105 earth and related environmental sciences, lcsh:R, Public Health, Environmental and Occupational Health, seafood consumption, medicine.disease, Blood mercury, Endocrinology, Autism spectrum disorder, autism spectrum disorder (ASD), blood mercury concentrations, Leafy vegetables, 030217 neurology & neurosurgery
Abstract

We investigated interactive roles of three metabolic glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1) and autism spectrum disorder (ASD) status in relation to blood Hg concentrations (BHC) of Jamaican children. We used data from 266 children (2-8 years) with ASD and their 1:1 age- and sex-matched typically developing (TD) controls. After adjusting General Linear Models for child’s age, socioeconomic status, consumption of leafy vegetables, fried plantain, canned fish, and the interaction between GSTP1 and GSTT1, we found significant interactions between GSTP1 and ASD status in relation to BHC either in a co-dominant or dominant genetic model for GSTP1(P &lt, 0.001, P = 0.007, respectively). In the co-dominant model for the Ile105Val GSTP1 polymorphism, geometric mean (GM) BHC in ASD cases with genotype Ile/Ile were significantly higher than in cases with the Ile/Val genotype (0.73 vs. 0.48 µg/L, P = 0.01). In contrast, in TD controls with the Ile/Val genotype GM BHC were significantly higher than in those with the Ile/Ile genotype (0.72 vs. 0.49 µg/L, P = 0.03) or the Val/Val genotype (0.72 vs. 0.51 µg/L, P = 0.04). Although our findings are consistent with the role of GSTP1 in detoxification of Hg, replication in other populations is warranted.

Published
2021
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27. A system for phenotype harmonization in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) program

Author

Tanika N. Kelly, May E Montasser, Alyna T. Khan, Laura M. Raffield, Carla Wilson, Elizabeth C. Oelsner, Kerri L. Wiggins, Ming-Huei Chen, Gina M. Peloso, Adolfo Correa, Andrew D. Johnson, Donna K. Arnett, Xiuqing Guo, Jai G. Broome, Daniel E. Weeks, Rebecca D. Jackson, Lucia Juarez, Stephen T. McGarvey, Pradeep Natarajan, Braxton D. Mitchell, Kent D. Taylor, Bruce M. Psaty, Santhi K Ganesh, Cathy C. Laurie, Nicola L. Hawley, Leslie S. Emery, Adrienne M. Stilp, Alanna C. Morrison, Jennifer A Smith, Charles Kooperberg, Catherine M. D’Augustine, Jan Graffelman, Paul S. de Vries, Chancellor Hohensee, Sharon L R Kardia, Patricia A Peyser, Wan-Ling Hsu, Erin J Buth, Kathleen C. Barnes, Susan R. Heckbert, Ramachandran S. Vasan, Nathan Pankratz, Karen M. Mutalik, Quenna Wong, Brian E. Cade, Jingmin Liu, Joshua C. Bis, Cecelia A. Laurie, Kari E. North, Fei Fei Wang, Mariza de Andrade, Nancy L. Heard-Costa, William Craig Johnson, L. Adrienne Cupples, Scott T. Weiss, Seyed Mehdi Nouraie, Patrick T. Ellinor, Jerome I. Rotter, Weiniu Gan, Shannon Kelly, Stephen S. Rich, Cashell E. Jaquish, Dongquan Chen, Nora Franceschini, Lisa R. Yanek, Jiwon Lee, Alexander P. Reiner, Megan L. Grove, Stella Aslibekyan, Myriam Fornage, Lawrence F Bielak, Rasika A. Mathias, Universitat Politècnica de Catalunya. Departament d'Estadística i Investigació Operativa, and Universitat Politècnica de Catalunya. COSDA-UPC - COmpositional and Spatial Data Analysis

Subjects
0301 basic medicine, Program evaluation, Computer science, Epidemiology, common data elements, hematologic disease, Matemàtiques i estadística::Matemàtica aplicada a les ciències [Àrees temàtiques de la UPC], Medical and Health Sciences, Mathematical Sciences, 0302 clinical medicine, Documentation, cardiovascular disease, and Blood Institute (U.S.), 030212 general & internal medicine, Phenomics, Precision Medicine, Lung, lung diseases, Sleep-wake disorders, phenotypes, 92 Biology and other natural sciences::92B Mathematical biology in general [Classificació AMS], Common data elements, Cardiovascular disease, Phenotype, Phenotypes, Biomatemàtica, Information Dissemination, Harmonization, 62 Statistics::62D05 Sampling theory, sample surveys [Classificació AMS], Hematologic disease, 03 medical and health sciences, Data Aggregation, Clinical Research, Controlled vocabulary, Genetics, Humans, AcademicSubjects/MED00860, sleep-wake disorders, Sampling (Statistics), Genetic Association Studies, Lung diseases, Biomathematics, Data collection, Study Design, Matemàtiques i estadística::Estadística aplicada::Estadística biosanitària [Àrees temàtiques de la UPC], Information dissemination, Human Genome, National Heart, Precision medicine, Data science, United States, 030104 developmental biology, Good Health and Well Being, National Heart, Lung, and Blood Institute (U.S.), Mostreig (Estadística), Program Evaluation
Abstract

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948–2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.

Published
2021

28. A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

Author

Han Chen, Peilin Jia, Megan L. Grove, Kari E. North, Yulin Dai, Alanna C. Morrison, Martha L. Daviglus, Elena V. Feofanova, Robert C. Kaplan, Eric Boerwinkle, Bing Yu, Qibin Qi, Jianwen Cai, and Cathy C. Laurie

Subjects
0301 basic medicine, Adult, Male, Population, Quantitative Trait Loci, Gene Expression, Genome-wide association study, Coronary Disease, Disease, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Metabolomics, Quantitative Trait, Heritable, Genetics, Metabolome, Humans, Vitamin E, Genetic Predisposition to Disease, Cytochrome P450 Family 4, Chromans, education, Genetics (clinical), education.field_of_study, Genome, Human, Membrane Transport Proteins, Hispanic or Latino, Heritability, Middle Aged, Cardiometabolic disease, 030104 developmental biology, Phenotype, Diabetes Mellitus, Type 2, Community health, Female, Public Health, Propionates, 030217 neurology & neurosurgery, Demography, Genome-Wide Association Study
Abstract

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%–54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10(−10), minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEV(range) = 1%–22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

Published
2020

29. Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Author

Jin Choul Chai, Amanda M. Fretts, Olga Garcia-Bedoya, Bharat Thyagarajan, Guo Chong Chen, Gregory A. Michelotti, Bing Yu, Jianwen Cai, Qibin Qi, Neil Schneiderman, Martha L. Daviglus, Megan L. Grove, Robert C. Kaplan, and Eric Boerwinkle

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Population, Medicine (miscellaneous), 030209 endocrinology & metabolism, Disease cluster, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, medicine, Diabetes Mellitus, Humans, Prospective Studies, education, Socioeconomic status, Aged, education.field_of_study, Sphingolipids, Nutrition and Dietetics, business.industry, Hispanic or Latino, Middle Aged, medicine.disease, Sphingolipid, United States, Original Research Communications, 030104 developmental biology, Community health, Cohort, Female, Animal studies, business
Abstract

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies. OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort. METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18–74 y who were free of diabetes and other major chronic diseases at baseline (2008–2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores. RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR (Q4 versus Q1) = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR (Q4 versus Q1) = 3.15; 95% CI: 1.75, 5.67; P-trend

Published
2020

30. Epigenetic age acceleration and cognitive function in African-American adults in midlife:The Atherosclerosis Risk in Communities Study

Author

Eric Boerwinkle, Rui Xia, Megan L. Grove, Thomas H. Mosley, Ian J. Deary, Rebecca F. Gottesman, Weihua Guan, Jan Bressler, Myriam Fornage, Rosie M. Walker, B. Gwen Windham, Andrew M. McIntosh, Kathryn L. Evans, Riccardo E. Marioni, and James S. Pankow

Subjects
Male, neuropsychological tests, Inverse Association, Aging, Time Factors, Population, Risk Assessment, Epigenesis, Genetic, Cognition, Medicine, Verbal fluency test, Humans, Association (psychology), education, Aged, General linear model, education.field_of_study, epigenetic age, business.industry, Confounding, THE JOURNAL OF GERONTOLOGY: Translational Section: DNA Methylation and Aging, verbal fluency, DNA methylation age, Middle Aged, Atherosclerosis, Black or African American, Cross-Sectional Studies, Biomarker (medicine), Female, Geriatrics and Gerontology, business, Demography
Abstract

Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual’s chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African American participants 47–70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a 1-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (β = −0.140 words; p = .001) and after adding other potential confounding variables (β = −0.104 words, p = .023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: β = −0.199 words; p = .034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: β = −0.110 words, p = .003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults.

Published
2020
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31. Publisher Correction: A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Author

Myriam Fornage, Thomas Meitinger, Elena Carnero-Montoro, Donna K. Arnett, Rory P. Wilson, Steve Horvath, Mina A. Jhun, Tao Zhang, Elias Salfati, Devin Absher, Marguerite R. Irvin, Melanie Waldenberger, Nona Sotoodehnia, Mohsen Ghanbari, Klodian Dhana, Christian Gieger, Stefan Gustafsson, Wei Chen, Andrea A. Baccarelli, Lifang Hou, Jeffrey R. O'Connell, Rui Xia, Jordana T. Bell, Bruce M. Psaty, Lars Lind, Yii-Der Ida Chen, Mohammad Arfan Ikram, May E. Montasser, Weihua Guan, Paula Singmann, Jincheng Shen, Eric Boerwinkle, Martina Müller-Nurasyid, Anh N. Do, Shengxu Li, Traci M. Bartz, Dianjianyi Sun, Eric A. Whitsel, Erik Ingelsson, Annette Peters, Jennifer A. Smith, Daniel Levy, Coleen M. Damcott, Xiaoping Zhao, Wei Zhao, Philip S. Tsao, Alan R. Shuldiner, Themistocles L. Assimes, Michael M. Mendelson, Tim D. Spector, Åsa K. Hedman, Chen Yao, Pfeiffer Liliane, Joyce B. J. van Meurs, Rahul Gondalia, Abbas Dehghan, Kim Valeska Emilie Braun, Roby Joehanes, Sharon L.R. Kardia, Erin B. Ware, Deugi Zhi, Megan L. Grove, Jennifer A. Brody, and André G. Uitterlinden

Subjects
Epigenomics, Adult, Male, Science, Quantitative Trait Loci, Ethnic group, General Physics and Astronomy, Blood lipids, Biology, General Biochemistry, Genetics and Molecular Biology, White People, Epigenesis, Genetic, Epigenome, Genetics, Leukocytes, Humans, Epigenetics, Dyslipidaemias, Aged, Multidisciplinary, Carnitine O-Palmitoyltransferase, General Chemistry, Hispanic or Latino, DNA Methylation, Middle Aged, Publisher Correction, Lipids, Black or African American, DNA methylation, CpG Islands, Female, Lipoproteins, HDL
Abstract

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.

Published
2021

32. Analysis of putative cis-regulatory elements regulating blood pressure variation

Author

Carlos Iribarren, Dongwon Lee, Aravinda Chakravarti, Eric Boerwinkle, Dilrini K. Ranatunga, Georg B. Ehret, Man Li, Dan E. Arking, Priyanka Nandakumar, Pui-Yan Kwok, Catherine Schaefer, Megan L. Grove, Neil Risch, and Thomas J. Hoffmann

Subjects
Aging, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Regulatory Sequences, Nucleic Acid, Cardiovascular, Kidney, Medical and Health Sciences, 0302 clinical medicine, Genotype, Gene expression, 2.1 Biological and endogenous factors, Aetiology, Association Studies Article, Genetics (clinical), Aorta, Genetics & Heredity, Genetics, Regulation of gene expression, 0303 health sciences, Intracellular Signaling Peptides and Proteins, Heart, General Medicine, Biological Sciences, Chromatin, Tibial Arteries, Regulatory sequence, Biotechnology, Cell type, Quantitative Trait Loci, Computational biology, Biology, 03 medical and health sciences, Humans, Molecular Biology, Gene, 030304 developmental biology, Genetic association, Nucleic Acid, Human Genome, Membrane Proteins, Atherosclerosis, Genetic epidemiology, Gene Expression Regulation, Expression quantitative trait loci, Regulatory Sequences, Genome-Wide Association Study
Abstract

Hundreds of loci have been associated with blood pressure traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ∼100,000 Genetic Epidemiology Research on Aging (GERA) study participants. In the present study, we subsequently focused on determining putative regulatory regions for these and other tissues of relevance to blood pressure, to both fine-map these loci by pinpointing genes and variants of functional interest within them, and to identify any novel genes.We constructed maps of putative cis-regulatory elements using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Sequence variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. In order to identify genes of interest, we aggregate these variants in these putative cis-regulatory elements within 50Kb of the start or end of genes considered as “expressed” in these tissues or cell types using publicly available gene expression data, and use the deltaSVM scores as weights in the well-known group-wise sequence kernel association test (SKAT). We test for association with both blood pressure traits as well as expression within these tissues or cell types of interest, and identify several genes, includingMTHFR,C10orf32,CSK,NOV,ULK4,SDCCAG8,SCAMP5,RPP25,HDGFRP3,VPS37B, andPPCDC. Although our study centers on blood pressure traits, we additionally examined two known genes,SCN5AandNOS1APinvolved in the cardiac trait QT interval, in the Atherosclerosis Risk in Communities Study (ARIC), as a positive control, and observed an expected heart-specific effect. Thus, our method may be used to identify variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.Author SummarySequence change in genes (“variants”) are linked to the presence and severity of different traits or diseases. However, as genes may be expressed in different tissues and at different times and degrees, using this information is expected to more accurately identify genes of interest. Variants within the genes are essential, but also in the sequences (“regulatory elements”) that control the genes’ expression in different tissues or cell types. In this study, we aim to use this information about expression and variants potentially involved in gene expression regulation to better pinpoint genes and variants in regulatory elements of interest for blood pressure regulation. We do so by taking advantage of such data that are publicly available, and use methods to combine information about variants in aggregate within a gene’s putative regulatory elements in tissues thought to be relevant for blood pressure, and identify several genes, meant to enable experimental follow-up.

Published
2019
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33. Methylome-Wide Association Study of Central Adiposity Implicate Genes Involved in Immune and Endocrine Systems

Author

Penny Gordon-Larsen, Phillip E. Melton, Yun Li, Ching-Ti Liu, Rae-Chi Huang, Rahul Gondalia, Eric Boerwinkle, Anne E. Justice, Karen N. Conneely, Lifang Hou, Ellen W. Demerath, Myriam Fornage, Daniel Levy, Annie Green Howard, Megan L. Grove, Geetha Chittoor, Kari E. North, James D. Stewart, L. Adrienne Cupples, Eric A. Whitsel, Andrea A. Baccarelli, Trevor A. Mori, Lawrence J. Beilin, Elise Lim, Lindsay Fernández-Rhodes, Weihua Guan, Nancy L. Heard-Costa, and Jan Bressler

Subjects
2. Zero hunger, 0303 health sciences, Waist, business.industry, Physiology, Methylation, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, CpG site, DNA methylation, Endocrine system, Medicine, business, Body mass index, 030217 neurology & neurosurgery, TXNIP, 030304 developmental biology
Abstract

We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist- to-hip ratio, and waist-to-height ratio adjusted for body mass index, in 2684 African American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated Cytosine-phosphate-Guanine methylation sites (CpGs) among adults using the Women’s Health Initiative and Framingham Heart Study participants (combined N=5743) and generalized associations in adolescents from The Raine Study (N=820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and 2 in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1, and RAP1GAP2 that had not previously been associated with obesity-related traits.

Published
2019
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34. Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs

Author

Josef Coresh, Adrienne Tin, Penglong Wang, Eliseo Guallar, Charles E. Newcomb, Ryan J. Longchamps, Jan Bressler, Brian O'Rourke, Traci M. Bartz, Kent D. Taylor, Nona Sotoodehnia, Eric Boerwinkle, James S. Pankow, Nathan Pankratz, Dan E. Arking, Christina A. Castellani, Daniel Levy, John A. Lane, Myriam Fornage, James S. Floyd, Megan L. Grove, Jennifer A. Brody, Chunyu Liu, and Jason A. Sumpter

Subjects
Genetics, 0303 health sciences, Mitochondrial DNA, Nuclear gene, Methylation, Biology, TFAM, Phenotype, 3. Good health, Nuclear DNA, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Gene expression, Gene, 030304 developmental biology
Abstract

BackgroundMitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.MethodsTo investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2,507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings we assayed an additional 2,528 participants from the Cardiovascular Health Study (CHS) (N=533) and Framingham Heart Study (FHS) (N=1,995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.ResultsThirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P-8). Meta-analysis across all cohorts identified six mtDNA-CN associated CpGs at genome-wide significance (P-8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN directly drives changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the ‘neuroactive ligand receptor interaction’ KEGG pathway was found to be highly overrepresented in the ARIC cohort (P= 5.24×10-12), as well as the TFAM knockout methylation (P=4.41×10-4) and expression (P=4.30×10-4) studies.ConclusionsThese results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

Published
2019
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35. Concentrations of Lead, Mercury, Arsenic, Cadmium, Manganese, and Aluminum in Blood of Romanian Children Suspected of Having Autism Spectrum Disorder

Author

Mohammad H. Rahbar, Iuliana Dobrescu, Mihaela G. Moisescu, L. Kobylinska, Maria Cristina Nedelcu, Christien Oktaviani Matei, Katherine A. Loveland, Megan L. Grove, Jan Bressler, Florina Rad, MacKinsey A. Bach, Ilinca Mihailescu, Manouchehr Hessabi, and Bogdan Mircea Matei

Subjects
inorganic chemicals, Male, mercury, cadmium, Autism Spectrum Disorder, Health, Toxicology and Mutagenesis, chemistry.chemical_element, lcsh:Medicine, Pilot Projects, Manganese, 010501 environmental sciences, 01 natural sciences, behavioral disciplines and activities, Article, Arsenic, 03 medical and health sciences, 0302 clinical medicine, Animal science, Limit of Detection, Metals, Heavy, mental disorders, Medicine, Humans, Child, 0105 earth and related environmental sciences, Cadmium, lead, Multivariable linear regression, business.industry, Romania, lcsh:R, Public Health, Environmental and Occupational Health, Mean age, Environmental exposure, Environmental Exposure, medicine.disease, 3. Good health, Mercury (element), chemistry, Autism spectrum disorder, aluminum, Child, Preschool, Female, business, 030217 neurology & neurosurgery
Abstract

Environmental exposure to lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) has been associated with neurodevelopmental disorders including autism spectrum disorder (ASD). We conducted a pilot study during May 2015&ndash, May 2107 to estimate blood concentrations of six metals (Pb, Hg, As, Cd, Mn, and Al) and identify their associated factors for children with ASD or suspected of having ASD in Romania. Sixty children, age 2&ndash, 8 years, were administered versions of ADOS or ADI-R translated from English to Romanian. After assessment, 2&ndash, 3 mL of blood was obtained and analyzed for the concentrations of the six metals. The mean age of children was 51.9 months and about 90% were male. More than half (65%) of the children were born in Bucharest. Over 90% of concentrations of As and Cd were below limits of detection. Geometric mean concentrations of Pb, Mn, Al, and Hg were 1.14 &mu, g/dL, 10.84 &mu, g/L, 14.44 &mu, g/L, and 0.35 &mu, g/L, respectively. Multivariable linear regression analysis revealed that children who were female, had less educated parents, exhibited pica, and ate cold breakfast (e.g., cereal), watermelon, and lamb had significantly higher concentrations of Pb compared to their respective referent categories (all p &lt, 0.05 except for eating lamb, which was marginally significant, p = 0.053). Although this is the first study that provides data on concentrations of the six metals for Romanian children with ASD, the findings from this study could be useful for designing future epidemiologic studies for investigating the role of these six metals in ASD in Romanian children.

Published
2019

36. Multiple SCN5A variant enhancers modulate its cardiac gene expression and the QT interval

Author

Luke Zhu, Eric Boerwinkle, Dongwon Lee, Dan E. Arking, Aravinda Chakravarti, Ashish Kapoor, Elsayed Z. Soliman, and Megan L. Grove

Subjects
Quantitative Trait Loci, Genome-wide association study, Locus (genetics), Biology, Regulatory Sequences, Nucleic Acid, QT interval, Cell Line, NAV1.5 Voltage-Gated Sodium Channel, Electrocardiography, Mice, Gene expression, Animals, Humans, Allele, Sequence variation, Enhancer, Alleles, Genetics, Multidisciplinary, Myocardium, Genetic Variation, Heart, Biological Sciences, Gene Expression Regulation, Cell culture, Genome-Wide Association Study
Abstract

The rationale for genome-wide association study (GWAS) results is sequence variation in cis -regulatory elements (CREs) modulating a target gene’s expression as the major cause of trait variation. To understand the complete molecular landscape of one of these GWAS loci, we performed in vitro reporter screens in cardiomyocyte cell lines for CREs overlapping nearly all common variants associated with any of five independent QT interval (QTi)-associated GWAS hits at the SCN5A - SCN10A locus. We identified 13 causal CRE variants using allelic reporter activity, cardiomyocyte nuclear extract-based binding assays, overlap with human cardiac tissue DNaseI hypersensitive regions, and predicted impact of sequence variants on DNaseI sensitivity. Our analyses identified at least one high-confidence causal CRE variant for each of the five sentinel hits that could collectively predict SCN5A cardiac gene expression and QTi association. Although all 13 variants could explain SCN5A gene expression, the highest statistical significance was obtained with seven variants (inclusive of the five above). Thus, multiple, causal, mutually associated CRE variants can underlie GWAS signals.

Published
2019

37. Interaction between manganese and GSTP1 in relation to autism spectrum disorder while controlling for exposure to mixture of lead, mercury, arsenic, and cadmium

Author

Eric Boerwinkle, Charlene Coore Desai, MacKinsey K.A. Christian, Maureen Samms-Vaughan, Jan Bressler, Jody Ann Reece, Manouchehr Hessabi, Sydonnie Shakespeare-Pellington, Wayne McLaughlin, Megan L. Grove, Katherine A. Loveland, Mohammad H. Rahbar, MinJae Lee, and Compton Beecher

Subjects
Cadmium, chemistry.chemical_element, Heavy metals, Manganese, 010501 environmental sciences, medicine.disease, 01 natural sciences, Article, Mercury (element), 03 medical and health sciences, Psychiatry and Mental health, Clinical Psychology, GSTP1, 0302 clinical medicine, chemistry, Autism spectrum disorder, Environmental health, mental disorders, Developmental and Educational Psychology, medicine, Autism, Psychology, 030217 neurology & neurosurgery, Arsenic, 0105 earth and related environmental sciences
Abstract

BACKGROUND: We previously reported a significant interactive association between polymorphisms of GSTP1 and blood manganese concentrations (BMC) with autism spectrum disorder (ASD) in Jamaican children. In this paper, we investigate the same interactive association with ASD while adjusting for the mixture of four metals (lead, mercury, cadmium, and arsenic). METHOD: We used data from 163 case-control pairs of children 2–8 years of age from our autism project in Jamaica, in which we collected blood for heavy metals analysis at enrollment. To minimize potential multicollinearity between concentrations of the four metals, we generated a mixture index using generalized weighted quantile sum regression, which was used in conditional logistic regression models to control for the four metals while assessing the interactive association between GSTP1 and BMC with ASD. RESULTS: Similar to the findings we reported previously, we found that in co-dominant and dominant models for GSTP1, among children with the Ile/Ile genotype, those with BMC > 12μg/L had 4.6 and 4.27 times higher odds of ASD compared to those with BMC < 12μg/L (adjusted Matched Odds Ratio (MOR) = 4.6, 95% CI: 1.21 – 17.42 and adjusted MOR = 4.27, 95% CI: 1.15 – 15.85, respectively). In the co-dominant model, for children with the Ile/Val and Val/Val genotypes, the adjusted MORs were 1.26 (95% CI: 0.32, 5.01) and 0.26 (95% CI: 0.05, 1.42), respectively. CONCLUSIONS: After adjusting for the mixture of four metals, the interactive association of BMC and GSTP1 with ASD remained significant with similar magnitude of associations. Results should be interpreted cautiously.

Published
2018

38. Contributions of rare coding variants in hypotension syndrome genes to population blood pressure variation

Author

Eric Boerwinkle, Priyanka Nandakumar, Aravinda Chakravarti, Alanna C. Morrison, and Megan L. Grove

Subjects
0301 basic medicine, Male, hypotension, Population, Observational Study, Black People, Blood Pressure, 030204 cardiovascular system & hematology, White People, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Risk Factors, Genetic variation, Exome Sequencing, epidemiologic studies, genomics, Medicine, Humans, Genetic Predisposition to Disease, Solute Carrier Family 12, Member 3, Prospective Studies, Potassium Channels, Inwardly Rectifying, Prospective cohort study, education, Allele frequency, Gene, Exome sequencing, Solute Carrier Family 12, Member 1, Genetics, education.field_of_study, business.industry, Genetic Variation, Reproducibility of Results, General Medicine, Middle Aged, 030104 developmental biology, Blood pressure, Phenotype, Hypertension, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, business, exome, Research Article
Abstract

Supplemental Digital Content is available in the text, Rare variants, in particular renal salt handling genes, contribute to monogenic forms of hypertension and hypotension syndromes with electrolyte abnormalities. A study by Ji et al (2008) demonstrated this effect for rare loss-of-function coding variants in SLC12A3 (NCCT), SLC12A1 (NKCC2), and KCNJ1 (ROMK) that led to reduction of ∼6 mm Hg for SBP and ∼3 mm Hg for DBP among carriers in 2492 European ancestry Framingham Heart Study (FHS) subjects. These findings support a potentially large role for these variants in interindividual variation in systolic and diastolic blood pressure (SBP, DBP) in the population. The present study focuses on replicating the analyses completed by Ji et al to identify effects of rare variants in the population-based Atherosclerosis Risk in Communities (ARIC) study. We attempted to replicate the findings by Ji et al by applying their criteria to identify putative loss-of-function variants with allele frequency

Published
2018

39. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Author

Ching-Ti Liu, Michael Boehnke, George Dedoussis, Sophie V. Eastwood, Ruth J. F. Loos, Keng-Hung Lin, Denis Rybin, Fredrik Karpe, Martina Müller-Nurasyid, Michael A. Province, Alison D. Murray, Bo Isomaa, Eirini Marouli, Konstantin Strauch, Michael Preuss, Paul M. Ridker, Jette Bork-Jensen, Albert V. Smith, Hugoline G. de Haan, Wayne Huey-Herng Sheu, Barbara Thorand, Wolfgang Rathmann, Lawrence F. Bielak, Peter Kovacs, Marit E. Jørgensen, Jennifer Wessel, Danish Saleheen, Jung-Jin Lee, James B. Meigs, Veikko Salomaa, Alena Stančáková, Tibor V. Varga, Hidetoshi Kitajima, Inês Barroso, Kent D. Taylor, Claudia Langenberg, Yoon Shin Cho, Joanna M. M. Howson, Andrew T. Hattersley, Marie-France Hivert, Markku Laakso, Kai-Uwe Eckardt, Bram P. Prins, Matthias B. Schulze, Andrew D. Morris, Susanne Jäger, Francis S. Collins, Kristi Läll, Xu Lin, Anette Varbo, Benjamin Lehne, Girish N. Nadkarni, Jonathan Marchini, Daniel I. Chasman, Michael Stumvoll, Mark O. Goodarzi, Cécile Lecoeur, Philippe M. Frossard, Noël P. Burtt, Frank Kee, Jasmina Kravic, Alain G. Bertoni, Ivan Brandslund, Najaf Amin, Lenore J. Launer, Oluf Pedersen, Johanna Kuusisto, Line Rode, Eleftheria Zeggini, Yingchang Lu, Markus Perola, Helen R. Warren, André G. Uitterlinden, Hanieh Yaghootkar, Torben Hansen, Harald Grallert, Annemari Käräjämäki, Abbas Dehghan, Gina M. Peloso, Yii-Der Ida Chen, Man Li, Shaofeng Huo, Lars Lind, Karen L. Mohlke, Adrienne Tin, Yang Hai, Renée de Mutsert, Gudmar Thorleifsson, Marie Moitry, Sune F. Nielsen, Sara M. Willems, Matthias Wuttke, Weihua Zhang, Young-Jin Kim, Giovanni Malerba, Richard A. Jensen, Loic Yengo, Mickaël Canouil, Kurt Lohman, Robert A. Scott, Tamara B. Harris, Ruifang Li-Gao, Florian Kronenberg, Anke Tönjes, Bok-Ghee Han, Krista Fischer, Thomas Meitinger, James S. Pankow, Jaakko Tuomilehto, Adam S. Butterworth, Jerome I. Rotter, Olov Rolandsson, Xiuqing Guo, Cramer Christensen, Marie Loh, Elizabeth Selvin, Bong-Jo Kim, Audrey Y. Chu, Reedik Mägi, Josée Dupuis, Anna Köttgen, Jean Ferrières, Jin Li, Robert Sladek, Leslie A. Lange, Niels Grarup, Roberta McKean-Cowdin, Cristen J. Willer, Jose C. Florez, Valgerdur Steinthorsdottir, Karina Meidtner, Annette Peters, Børge G. Nordestgaard, Rajiv Chowdhury, Ioanna Ntalla, Emma Ahlqvist, Leif Groop, Nicholas J. Wareham, Kerrin S. Small, Tiinamaija Tuomi, Cecilia M. Lindgren, Katharine R. Owen, Giovanni Gambaro, Cornelia M. van Duijn, Dennis O. Mook-Kanamori, Kenneth Rice, Erik Ingelsson, Colin N. A. Palmer, Sharon L.R. Kardia, Neil R. Robertson, Dajiang J. Liu, Sebastian Schönherr, Daniel Taliun, Sekar Kathiresan, James G. Wilson, Ping An, Patricia A. Peyser, Matthias Blüher, Frits R. Rosendaal, John C. Chambers, Caroline Hayward, Shoaib Afzal, Fernando Rivadineira, Marielisa Graff, Pranav Yajnik, Vasiliki Mamakou, Juan Fernandez Tajes, Stefan Gustafsson, Heather M. Highland, Vilmantas Giedraitis, Andrew R. Wood, Saima Afaq, Jaspal S. Kooner, Megan L. Grove, Jennifer A. Brody, Andrew P. Morris, James P. Cook, Praveen Surendran, Jennifer Kriebel, Heikki A. Koistinen, Kari Stefansson, Anders Rosengren, Rainer Rauramaa, Satu Männistö, Oscar H. Franco, Yongmei Liu, N. William Rayner, Blair H. Smith, Erwin P. Bottinger, Ayse Demirkan, Allan Linneberg, Jonathan Marten, Huaixing Li, Sung Soo Kim, Sophie Hackinger, Cristina Bombieri, Lia B. Bang, Jun Liu, Asif Rasheed, Tim D. Spector, Paul W. Franks, Mark I. McCarthy, Heiner Boeing, Anne E. Justice, Vilmundur Gudnason, Sohee Han, Unnur Thorsteinsdottir, Panos Deloukas, Naveed Sattar, Eric Boerwinkle, Martin Ingelsson, John Danesh, Vassily Trubetskoy, Marco M Ferrario, Marju Orho-Melander, Wei Gan, Philippe Froguel, Symen Ligthart, Susan R. Heckbert, Jie Yao, Anne Tybjærg-Hansen, Robin Young, Daniel R. Witte, Anubha Mahajan, Peter Almgren, Timothy M. Frayling, Tanya M. Teslovich, Matt Neville, Philippe Amouyel, Wei Zhao, Andres Metspalu, Yao Hu, Olle Melander, Kari Kuulasmaa, Jason Flannick, Torben Jørgensen, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Rohit Varma, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Male, Inference, Genome-wide association study, Whole Exome Sequencing, 0302 clinical medicine, type 2 diabetes, coding variant associations signals, mechanistic inference, fine mapping, Coding region, Chromosome Mapping/statistics & numerical data, European Continental Ancestry Group/genetics, CONFERS SUSCEPTIBILITY, Exome sequencing, 11 Medical and Health Sciences, Genetics, Genetics & Heredity, 0303 health sciences, MAGIC Consortium, Chromosome Mapping, Whole Exome Sequencing/statistics & numerical data, Identification (information), RARE VARIANTS, LOW-FREQUENCY, Female, ExomeBP Consortium, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Posterior probability, European Continental Ancestry Group, 030209 endocrinology & metabolism, Context (language use), Computational biology, Biology, GENOTYPE IMPUTATION, Article, White People, GENETIC ARCHITECTURE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, QUALITY-CONTROL, Exome Sequencing, Genome-Wide Association Study/statistics & numerical data, Journal Article, GIANT Consortium, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Alleles, Genetic association, 030304 developmental biology, FATTY LIVER-DISEASE, Science & Technology, Genetic Variation, 06 Biological Sciences, Genetic architecture, Minor allele frequency, BODY-MASS INDEX, 030104 developmental biology, Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 2/classification, 030217 neurology & neurosurgery, Coding (social sciences), Genome-Wide Association Study, Developmental Biology
Abstract

Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated coding variant data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p−7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency 1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these associated coding variants in their regional context, with and without additional weighting to account for the global enrichment of complex trait association signals in coding exons. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent “false leads” and naïve analysis could have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.

Published
2018
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40. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center

Subjects
0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018
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41. An epigenome-wide study of obesity in African American youth and young adults: novel findings, replication in neutrophils, and relationship with gene expression

Author

Kari E. North, Xiaoling Wang, Yisong Huang, Shaoyong Su, Harold Snieder, Vernon A. Barnes, Ellen W. Demerath, Weihua Guan, Huidong Shi, Megan L. Grove, Guang Hao, Yue Pan, Yanbin Dong, Haidong Zhu, James S. Pankow, and Life Course Epidemiology (LCE)

Subjects
0301 basic medicine, Epigenomics, Male, Youth, Neutrophils, LOCI, lcsh:Medicine, Genome-wide association study, 030204 cardiovascular system & hematology, DISEASE, 0302 clinical medicine, Leukocytes, Gene Regulatory Networks, Genetics (clinical), Regulation of gene expression, African Americans, DNA methylation, ASSOCIATION, 3. Good health, EPIGENETICS, CpG site, Female, ADIPOSITY, WAIST CIRCUMFERENCE, Adult, Adolescent, lcsh:QH426-470, Biology, 03 medical and health sciences, Young Adult, MICROARRAY, Genetics, Humans, Epigenetics, Obesity, Molecular Biology, Gene Expression Profiling, Research, lcsh:R, Epigenome, Gene expression profiling, Black or African American, BODY-MASS INDEX, lcsh:Genetics, 030104 developmental biology, Gene Expression Regulation, Immunology, CpG Islands, Developmental Biology, Genome-Wide Association Study, RESPONSES
Abstract

Background We conducted an epigenome-wide association study (EWAS) on obesity in healthy youth and young adults and further examined to what extent identified signals influenced gene expression and were independent of cell type composition and obesity-related cardio-metabolic risk factors. Genome-wide DNA methylation data from leukocytes were obtained from 700 African Americans aged 14–36. We also measured genome-wide DNA methylation data from neutrophils as well as genome-wide gene expression data from leukocytes in a subset of samples (n = 188). Results The EWAS identified 76 obesity-related CpG sites in leukocytes with p

Published
2018

42. Novel associations between blood DNA methylation and body mass index in middle-Aged and older adults

Author

Daniel D. Buchanan, Ellen W. Demerath, Gianluca Severi, Daniel F. Schmidt, Steve Nguyen, Weihua Guan, Julie K. Bassett, Pierre Antoine Dugué, Helen Tsimiklis, Graham G. Giles, Jihoon E. Joo, Dallas R. English, Melissa C. Southey, Robert J. MacInnis, Y. M. Geurts, James S. Pankow, Enes Makalic, John L. Hopper, Ee Ming Wong, Roger L. Milne, Chol-Hee Jung, Laura Baglietto, Allison M. Hodge, Liesel M. FitzGerald, and Megan L. Grove

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Body Mass Index, 03 medical and health sciences, Insulin resistance, Endocrinology, Internal medicine, Neoplasms, medicine, Humans, Gene Regulatory Networks, Epigenetics, Nutrition and Dietetics, Aged, business.industry, Confounding, Australia, Methylation, DNA, DNA Methylation, Middle Aged, medicine.disease, Diabetes and Metabolism, 030104 developmental biology, Cross-Sectional Studies, DNA methylation, Female, business, Body mass index, Cohort study, Genome-Wide Association Study
Abstract

There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case–control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. Cross-sectional analysis identified 310 CpGs associated with BMI with P

Published
2018

43. Concentration of Lead, Mercury, Cadmium, Aluminum, Arsenic and Manganese in Umbilical Cord Blood of Jamaican Newborns

Author

Charlene Coore Desai, Renee Morgan, Katherine A. Loveland, Megan L. Grove, Eric Boerwinkle, Mohammad H. Rahbar, Jan Bressler, Manouchehr Hessabi, Sydonnie Shakespeare-Pellington, Maureen Samms-Vaughan, Jody Ann Reece, and Aisha S. Dickerson

Subjects
Adult, Male, medicine.medical_specialty, Jamaica, mercury, newborns, cadmium, Health, Toxicology and Mutagenesis, Birth weight, Population, chemistry.chemical_element, Physiology, lcsh:Medicine, Umbilical cord, Article, Young Adult, Pregnancy, Metals, Heavy, medicine, Birth Weight, Humans, education, Arsenic, Cadmium, education.field_of_study, lead, business.industry, lcsh:R, Infant, Newborn, Public Health, Environmental and Occupational Health, arsenic, Fetal Blood, medicine.disease, 3. Good health, Surgery, Mercury (element), medicine.anatomical_structure, chemistry, Cord blood, aluminum, Linear Models, manganese, cord blood, Female, business
Abstract

The objective of this study was to characterize the concentrations of lead, mercury, cadmium, aluminum, and manganese in umbilical cord blood of Jamaican newborns and to explore the possible association between concentrations of these elements and certain birth outcomes. Based on data from 100 pregnant mothers and their 100 newborns who were enrolled from Jamaica in 2011, the arithmetic mean (standard deviation) concentrations of cord blood lead, mercury, aluminum, and manganese were 0.8 (1.3 μg/dL), 4.4 (2.4 μg/L), 10.9 (9.2 μg/L), and 43.7 (17.7 μg/L), respectively. In univariable General Linear Models, the geometric mean cord blood aluminum concentration was higher for children whose mothers had completed their education up to high school compared to those whose mothers had any education beyond high school (12.2 μg/L vs. 6.4 μg/L, p &lt, 0.01). After controlling for maternal education level and socio-economic status (through ownership of a family car), the cord blood lead concentration was significantly associated with head circumference (adjusted p &lt, 0.01). Our results not only provide levels of arsenic and the aforementioned metals in cord blood that could serve as a reference for the Jamaican population, but also replicate previously reported significant associations between cord blood lead concentrations and head circumference at birth in other populations.

Published
2015

44. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD

Subjects
0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract

International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017
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45. The diagnosis of autism and autism spectrum disorder in Low and Middle Income Countries: Experience from Jamaica

Author

Maureen Samms-Vaughan, Charlene Coore-Desai, Jan Bressler, Megan L. Grove, Manouchehr Hessabi, Deborah A. Pearson, Sydonnie Shakespeare-Pellington, Eric Boerwinkle, Jody Ann Reece, Mohammad H. Rahbar, Katherine A. Loveland, and Aisha S. Dickerson

Subjects
Male, medicine.medical_specialty, Jamaica, Autism Spectrum Disorder, Test validity, behavioral disciplines and activities, Article, Autism Diagnostic Observation Schedule, 03 medical and health sciences, 0302 clinical medicine, Rating scale, mental disorders, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Psychiatry, Child, Developing Countries, Poverty, Analysis of Variance, 05 social sciences, Mean age, medicine.disease, Autism spectrum disorder, Low and middle income countries, Child, Preschool, Childhood Autism Rating Scale, Autism, Female, Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Clinical psychology
Abstract

The administration requirements of the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview–Revised, widely used in high-income countries, make them less feasible for diagnosis of autism spectrum disorder in low- and middle-income countries. The flexible administration requirements of the Childhood Autism Rating Scale have resulted in its use in both high-income countries and low- and middle-income countries. This study examines the agreement between assessments using the Childhood Autism Rating Scale with those using the Autism Diagnostic Observation Schedule or Autism Diagnostic Observation Schedule, Second Edition and Autism Diagnostic Interview–Revised in Jamaica. Children aged 2–8 years (n = 149) diagnosed with autism by an experienced clinician using the Childhood Autism Rating Scale were re-evaluated using the Autism Diagnostic Observation Schedule and Autism Diagnostic Interview–Revised. The proportion diagnosed with autism spectrum disorder using the Autism Diagnostic Observation Schedule, Autism Diagnostic Observation Schedule, Second Edition, and Autism Diagnostic Interview–Revised was determined and mean domain scores compared using analysis of variance (ANOVA). The mean age was 64.4 (standard deviation = 21.6) months; the male:female ratio was 6:1. The diagnostic agreement of the Childhood Autism Rating Scale with the Autism Diagnostic Observation Schedule and Autism Diagnostic Observation Schedule, Second Edition was 100.0% and 98.0%, respectively. Agreement with the Autism Diagnostic Interview–Revised was 94.6%. Domain scores were highest for children with more severe symptoms (p

Published
2017

46. Exome-wide association study of plasma lipids in >300,000 individuals

Author

Asif Rasheed, Mary F. Feitosa, Ian J. Deary, Melissa E. Garcia, Danish Saleheen, Christian Gieger, Andrea Maschio, Lia E. Bang, Cliona Molony, Ivan Brandslund, Dan M. Roden, Ian Ford, Paul M. Ridker, Alisa K. Manning, Giorgio Pistis, Anette Varbo, Alexander P. Reiner, Kathleen Stirrups, David C. Liewald, Tim D. Spector, Paul W. Franks, Cristen J. Willer, Daniel I. Chasman, Jean Ferrières, Vilmundur Gudnason, Tapani Ebeling, Neil Poulter, Magdalena Zoledziewska, Elizabeth K. Speliotes, Eleftheria Zeggini, Megan L. Grove, Hua Tang, Stavroula Kanoni, Peter Weeke, Panos Deloukas, Daniel J. Rader, Amit Khera, Serena Sanna, Dorota Pasko, Gina M. Peloso, Charles Kooperberg, Suthesh Sivapalaratnam, Natalie R. van Zuydam, Christian M. Shaffer, Fredrik Karpe, Naveed Sattar, Pieter Muntendam, Ruth J. F. Loos, Eric Boerwinkle, Wei Gao, Mark J. Caulfield, Matt Neville, Sangeetha Somayajula, Olle Melander, Hayato Tada, Jose M. Ordovas, He Zhang, John D. Rioux, Michael Boehnke, Erwin P. Bottinger, Franco Giulianini, Martina Müller-Nurasyid, Stella Trompet, Connor A. Emdin, Andrew P. Morris, Johanne Marie Justesen, Alan R. Tall, Kari Kuulasmaa, Adam S. Butterworth, Marie-Pierre Dubé, Dajiang J. Liu, Paul L. Auer, Jennifer E. Huffman, Usman Baber, John Danesh, Xiao Wang, Anna F. Dominiczak, Jarmo Virtamo, John M. Starr, Ozren Polasek, Gonçalo R. Abecasis, Timo A. Lakka, Stephen S. Rich, Marco M Ferrario, Marju Orho-Melander, Xueling Sim, Dominique Arveiler, Dermot F. Reilly, Torsten Lauritzen, Gudny Eiriksdottir, Marit E. Jørgensen, Anubha Mahajan, Colin N. A. Palmer, Veikko Salomaa, Nicholas J. Wareham, Dewan S. Alam, Anne Tybjærg-Hansen, Ellen M. Schmidt, Y. Eugene Chen, Heather M. Stringham, Bruce M. Psaty, Christie M. Ballantyne, Nan Wang, Joshua C. Bis, Myriam Fornage, Neil S Zheng, Kristian Hveem, Praveen Surendran, Yingchang Lu, Peter S. Sever, James B. Meigs, Heikki A. Koistinen, Charlotta Pisinger, Tibor V. Varga, Yii-Der Ida Chen, Konstantin Strauch, Timothy M. Frayling, Patricia B. Munroe, Albert V. Smith, Ruth Frikke-Schmidt, Lorraine Southam, Frida Renström, Philippe Amouyel, Nicholas G. D. Masca, Alexessander Couto Alves, Xiangfeng Lu, Andres Metspalu, Anne Langsted, Joanna M. M. Howson, Tamara B. Harris, Leif Groop, Chad A. Cowan, Cramer Christensen, Audrey Y. Chu, Markku Laakso, Torben Hansen, Li-An Lin, John C. Chambers, Jonas B. Nielsen, Niels Grarup, Neil R. Robertson, Kiran Musunuru, Joshua S. Weinstock, Morris J. Brown, Jean-Claude Tardif, Gorm B. Jensen, Jerome I. Rotter, Harald Grallert, Yan Zhang, Kerrin S. Small, Nathan O. Stitziel, Fabio Busonero, Jennifer Wessel, Themistocles L. Assimes, Lenore J. Launer, Lars G. Fritsche, Mark O. Goodarzi, Peter W.F. Wilson, Sekar Kathiresan, Philippe M. Frossard, Emanuele Di Angelantonio, Yanhua Zhou, James G. Wilson, Frank Kee, Scott M. Damrauer, Weihua Zhang, Gail Davies, Oluf Pedersen, Sune F. Nielsen, Alanna C. Morrison, Raquel S. Sevilla, Helen R. Warren, Johanna Kuusisto, Hanieh Yaghootkar, Sandosh Padmanabhan, Philip S. Tsao, Caroline Hayward, Tõnu Esko, Ming Xu, Anders Mälarstig, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, Robin Young, C.J. O'Donnell, Yong Huo, Melanie Waldenberger, Jaspal S. Kooner, Pekka Mäntyselkä, Marjo-Riitta Järvelin, Santhi K. Ganesh, Annette Peters, L. Adrienne Cupples, Wei Zhou, Derek Klarin, Markus Perola, Francesco Cucca, Allan Linneberg, Mark I. McCarthy, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, J. Wouter Jukema, Valentin Fuster, Claudia Langenberg, Roxana Mehran, Børge G. Nordestgaard, Jaakko Tuomilehto, Reedik Mägi, Blair H. Smith, Johanna Jakobsdottir, Marianne Benn, Kent D. Taylor, Ani Manichaikul, Igor Rudan, Aniruddh P. Patel, Joshua C. Denny, Oddgeir L. Holmen, John M. C. Connell, Robert A. Scott, Haojie Yu, Rajiv Chowdhury, Sehrish Jabeen, Antonella Mulas, Aliki-Eleni Farmaki, Rainer Rauramaa, George Dedoussis, Vascular Medicine, Nielsen, Jonas B [0000-0002-6654-2852], Kathiresan, Sekar [0000-0002-6724-032X], Apollo - University of Cambridge Repository, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
0301 basic medicine, Exome/genetics, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Charge Diabetes Working Group, Macular Degeneration, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Exome, Macular Degeneration/blood, Genetics & Heredity, Genetic Predisposition to Disease/genetics, CLONAL HEMATOPOIESIS, 11 Medical And Health Sciences, CODING-SEQUENCE VARIANTS, Lipids, Phenotype, CARDIOVASCULAR-DISEASE, VA Million Veteran Program, lipids (amino acids, peptides, and proteins), GOLD Consortium, LOW-FREQUENCY, EPIC-InterAct Consortium, Diabetes Mellitus, Type 2/blood, Life Sciences & Biomedicine, Type 2, medicine.medical_specialty, Genotype, APOBEC-1 COMPLEMENTATION FACTOR, Biology, Lower risk, Article, EPIC-CVD Consortium, GENETIC ARCHITECTURE, 03 medical and health sciences, Coronary Artery Disease/blood, Diabetes mellitus, Internal medicine, Genetics, medicine, Diabetes Mellitus, Journal Article, Lipolysis, Humans, Genetic Predisposition to Disease, Allele, TYROSINE KINASE JAK2, Genetic Association Studies, B MESSENGER-RNA, Science & Technology, MACULAR DEGENERATION, MYELOPROLIFERATIVE DISORDERS, Cholesterol, Lipids/blood, Genetic Variation, 06 Biological Sciences, medicine.disease, cardiovascular diseases, genome wide association studies, Genetic Association Studies/methods, 030104 developmental biology, Endocrinology, chemistry, Diabetes Mellitus, Type 2, TM6SF2, Developmental Biology
Abstract

We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.

Published
2017
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47. Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease : A Mendelian Randomization Approach

Author

Ariella Cohain, Weihua Guan, Caroline S. Fox, Allan F. McRae, Lee Murphy, Daniele Fallin, Degui Zhi, Tianxiao Huan, Brian H. Chen, John M. Starr, Kari E. North, Andrew P. Feinberg, Michael L. Multhaup, Devin Absher, Sonia Shah, Erica L. Kleinbrink, Eric E. Schadt, Michael M. Mendelson, Jude Gibson, Roby Joehanes, Paul Redmond, Daniel Levy, Jan Bressler, Ronald M. Krauss, Peter M. Visscher, Erik Ingelsson, Stella Aslibekyan, James S. Pankow, Myriam Fornage, Leonard Lipovich, Stefan Gustafsson, Lars Lind, Donna K. Arnett, Johan Sundström, Naomi R. Wray, Riccardo E. Marioni, Eric Boerwinkle, Christine M. Willinger, Paul Courchesne, Janie Corley, Åsa K. Hedman, Chunyu Liu, Sarah E. Harris, Ellen W. Demerath, Ian J. Deary, Marguerite R. Irvin, Megan L. Grove, Liming Liang, Chen Yao, and Lewis, Cathryn

Subjects
0301 basic medicine, Male, Medicin och hälsovetenskap, Physiology, Genome-wide association study, Coronary Artery Disease, Bioinformatics, Cardiovascular, Biochemistry, Medical and Health Sciences, Epigenesis, Genetic, Body Mass Index, 0302 clinical medicine, Medicine and Health Sciences, Leukocytes, 2.1 Biological and endogenous factors, Aetiology, Cancer, Oligonucleotide Array Sequence Analysis, 2. Zero hunger, Regulation of gene expression, Genetics, education.field_of_study, DNA methylation, Mendelian Randomization Analysis, General Medicine, Methylation, Hematology, Chromatin, 3. Good health, Body Fluids, Nucleic acids, Blood, Heart Disease, Physiological Parameters, 030220 oncology & carcinogenesis, Medicine, Epigenetics, Female, Anatomy, DNA modification, Chromatin modification, Research Article, Chromosome biology, Cell biology, Population, Biology, DNA replication, 03 medical and health sciences, Genetic, Clinical Research, General & Internal Medicine, Mendelian randomization, Humans, Obesity, education, Metabolic and endocrine, Nutrition, Aged, Biology and life sciences, Body Weight, DNA, DNA Methylation, Lipid Metabolism, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, Gene expression, Generic health relevance, Epigenesis, Genome-Wide Association Study
Abstract

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases., Daniel Levy and colleagues examine mechanisms that could link body mass index to cardiovascular diseases via gene expression., Author Summary Why Was This Study Done? Genetic sequence variants explain only a modest proportion of the variation in body mass index (BMI) and cardiometabolic disease in the general population. There is limited understanding of the link of DNA methylation—a well-characterized epigenetic modification—with BMI and cardiometabolic disease in the general population. What Did the Researchers Do and Find? We conducted a cross-sectional analysis of the association of BMI with leukocyte DNA methylation at over 400,000 sites in the genome among 7,798 community-dwelling adults. We identified associations between BMI and methylation at 83 replicated sites (including 50 novel sites) and concurrent differences in expression in whole blood of genes overrepresented in lipid metabolism pathways. Using genetic sequence variants to model exposure to differential DNA methylation and tissue-specific gene expression, we found differential methylation and expression of SREBF1 to be implicated in BMI, adiposity-related traits, and coronary artery disease. Using genetic sequence variants to model exposure to differences in BMI, we found a substantial proportion of the differentially methylated sites (16 of 83) to be downstream of BMI. What Do These Findings Mean? Evidence is accumulating that epigenetic modifications, such as DNA methylation, are related to obesity-related diseases in the general population. We provide support for a role of genomic regulation of a lipid metabolism transcription factor, SREBF1, in adiposity and coronary artery disease. Mendelian randomization approaches can help prioritize relevant loci for future functional studies, but the cross-sectional observational nature of our study limits definitive causal inference.

Published
2017
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48. MicroRNAs in the miR-17 and miR-15 families are downregulated in chronic kidney disease with hypertension

Author

Adrienne Tin, Jianzhong Ma, Priyanka Nandakumar, Aravinda Chakravarti, Josef Coresh, Eric Boerwinkle, and Megan L. Grove

Subjects
0301 basic medicine, Male, Physiology, Blood Pressure, Gastroenterology, Biochemistry, Vascular Medicine, Chronic Kidney Disease, Medicine and Health Sciences, Gene Regulatory Networks, Geriatric Nephrology, 2. Zero hunger, Multidisciplinary, Middle Aged, 3. Good health, Body Fluids, Nucleic acids, Blood, Nephrology, Hypertension, Medicine, Female, medicine.symptom, Anatomy, Network Analysis, Research Article, medicine.medical_specialty, Computer and Information Sciences, Science, Diastole, Renal function, Down-Regulation, Inflammation, 03 medical and health sciences, Immune system, Diabetes mellitus, Internal medicine, medicine, Genetics, Humans, RNA, Messenger, Renal Insufficiency, Chronic, Non-coding RNA, Biology and life sciences, business.industry, Sequence Analysis, RNA, Gene Expression Profiling, Kidneys, Renal System, medicine.disease, Gene regulation, MicroRNAs, 030104 developmental biology, Blood pressure, Gene Ontology, Geriatrics, RNA, Gene expression, business, Body mass index, Kidney disease
Abstract

BackgroundIn older adults (aged 70-74 years), African-Americans have 4-fold higher risk of developing hypertension-attributed end-stage renal disease (ESRD) than European-Americans. A hypothesized mechanism linking hypertension and progressive chronic kidney disease (CKD) is the innate immune response and inflammation. Persons with CKD are also more susceptible to infection. Gene expression in peripheral blood can provide a view of the innate immune activation profile. We aimed to identify differentially expressed genes, microRNAs, and pathways in peripheral blood between cases with CKD and high blood pressure under hypertension treatment versus controls without CKD and with controlled blood pressure in African Americans.MethodsCase and control pairs (N = 15x2) were selected from those without diabetes and were matched for age, sex, body mass index, APOL1 risk allele count, and hypertension medication use. High blood pressure under hypertension treatment was defined as hypertension medication use and systolic blood pressure (SBP) ≥ 145 mmHg. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. Cases were selected from those with CKD and high blood pressure under hypertension treatment, and controls were selected from those without CKD (eGFR: 75-120 mL/min/1.73m2 and urine albumin-to-creatinine ratio < 30mg/g) and with blood pressure controlled by hypertension medication use (SBP < 135 mmHg and D(diastolic)BP < 90 mm Hg). We perform RNA sequencing of mRNA and microRNA and conducted differential expression and co-expression network analysis.ResultsOf 347 miRNAs included in the analysis, 14 were significantly associated with case status (Benjamini-Hochberg adjusted p-value [BH p] < 0.05). Of these, ten were downregulated in cases: three of each belong to the miR-17 and miR-15 families. In co-expression network analysis of miRNA, one module, which included 13 of the 14 significant miRNAs, had significant association with case status. Of the 14,488 genes and 41,739 transcripts included in the analysis, none had significant association with case status. Gene co-expression network analyses did not yield any significant associations for mRNA.ConclusionWe have identified 14 differentially expressed miRNAs in the peripheral blood of CKD cases with high blood pressure under hypertension treatment as compared to appropriate controls. Most of the significant miRNAs were downregulated and have critical roles in immune cell functions. Future studies are needed to replicate our findings and determine whether the downregulation of these miRNAs in immune cells may influence CKD progression or complications.

Published
2017

49. Rare coding variants associated with blood pressure variation in 15 914 individuals of African ancestry

Author

Aravinda Chakravarti, C. Charles Gu, Alanna C. Morrison, Melissa A. Richard, Adesola Ogunniyi, Fasil Tekola-Ayele, Sharon L.R. Kardia, Bamidele O. Tayo, Erin B. Ware, Richard S. Cooper, Yun J. Sung, Babatunde L. Salako, Georg Ehret, Priyanka Nandakumar, Megan L. Grove, Dongwon Lee, Charles N. Rotimi, and Myriam Fornage

Subjects
0301 basic medicine, Candidate gene, Blood Pressure/genetics, Genotype, Physiology, Population, Black People, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetic variation, Internal Medicine, Cardiovascular Diseases/genetics, Medicine, Humans, Exome, Risk factor, education, Genotyping, Genetics, ddc:616, education.field_of_study, business.industry, African Continental Ancestry Group/genetics, Genetic Variation, 030104 developmental biology, Genetic epidemiology, Cardiovascular Diseases, Hypertension, Cardiology and Cardiovascular Medicine, business, Hypertension/genetics, Cohort study
Abstract

Hypertension is a major risk factor for all cardiovascular diseases, especially among African Americans. This study focuses on identifying specific blood pressure (BP) genes using 15 914 individuals of African ancestry from eight cohorts (Africa America Diabetes Mellitus, Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in young Adults, Genetics Network, Genetic Epidemiology Network of Arteriopathy, Howard University Family Study, Hypertension Genetic Epidemiology Network, and Loyola University Chicago Cohort) to further genetic findings in this population which has generally been underrepresented in BP studies. We genotyped and performed various single variant and gene-based exome-wide analyses on 15 914 individuals on the Illumina HumanExome Beadchip v1.0 or v1.1 to test association with SBP and DBP long-term average residuals that were adjusted for age, age-squared, sex, and BMI. We identified rare variants affecting SBP and DBP in 10 genes: AFF1, GAPDHS, SLC28A3, COL6A1, CRYBA2, KRBA1, SEL1L3, YOD1, CCDC13, and QSOX1. Prior experimental evidence for six of these 10 candidate genes supports their involvement in cardiovascular mechanisms, corroborating their potential roles in BP regulation. Although our results require replication or validation due to their low numbers of carriers, and an ethnicity-specific genotyping array may be more informative, this study, which has identified several candidate genes in this population most susceptible to hypertension, presents one of the largest African-ancestry BP studies to date and the largest including analysis of rare variants.

Published
2017

50. Role of Metabolic Genes in Blood Arsenic Concentrations of Jamaican Children with and without Autism Spectrum Disorder

Author

Aisha S. Dickerson, Jianzhong Ma, Eric Boerwinkle, Jan Bressler, Katherine A. Loveland, Maureen Samms-Vaughan, Wayne McLaughlin, Megan L. Grove, Mohammad H. Rahbar, Manouchehr Ardjomand-Hessabi, Compton Beecher, and Sydonnie Shakespeare-Pellington

Subjects
Adult, Male, Jamaica, Health, Toxicology and Mutagenesis, glutathione S-transferase (GST) genes, Physiology, chemistry.chemical_element, lcsh:Medicine, Biology, Article, GSTP1, Genotype, medicine, Humans, Genetic Predisposition to Disease, detoxification, Adverse effect, Child, Arsenic, Whole blood, Glutathione Transferase, Genetics, Polymorphism, Genetic, Confounding, lcsh:R, Public Health, Environmental and Occupational Health, Case-control study, arsenic, interactions, medicine.disease, 3. Good health, chemistry, Glutathione S-Transferase pi, Autism spectrum disorder, Child Development Disorders, Pervasive, Case-Control Studies, Child, Preschool, autism spectrum disorder (ASD), Female, Multiplex Polymerase Chain Reaction
Abstract

Arsenic is a toxic metalloid with known adverse effects on human health. Glutathione-S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. We investigated the association between GST genotypes and whole blood arsenic concentrations (BASC) in Jamaican children with and without autism spectrum disorder (ASD). We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2–8 years) from Jamaica. Using log-transformed BASC as the dependent variable in a General Linear Model, we observed a significant interaction between GSTP1 and ASD case status while controlling for several confounding variables. However, for GSTT1 and GSTM1 we did not observe any significant associations with BASC. Our findings indicate that TD children who had the Ile/Ile or Ile/Val genotype for GSTP1 had a significantly higher geometric mean BASC than those with genotype Val/Val (3.67 µg/L vs. 2.69 µg/L, p < 0.01). Although, among the ASD cases, this difference was not statistically significant, the direction of the observed difference was consistent with that of the TD control children. These findings suggest a possible role of GSTP1 in the detoxification of arsenic.

Published
2014

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