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1. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Author

Keener, Rebecca, Chhetri, Surya B, Connelly, Carla J, Taub, Margaret A, Conomos, Matthew P, Weinstock, Joshua, Ni, Bohan, Strober, Benjamin, Aslibekyan, Stella, Auer, Paul L, Barwick, Lucas, Becker, Lewis C, Blangero, John, Bleecker, Eugene R, Brody, Jennifer A, Cade, Brian E, Celedon, Juan C, Chang, Yi-Cheng, Cupples, L Adrienne, Custer, Brian, Freedman, Barry I, Gladwin, Mark T, Heckbert, Susan R, Hou, Lifang, Irvin, Marguerite R, Isasi, Carmen R, Johnsen, Jill M, Kenny, Eimear E, Kooperberg, Charles, Minster, Ryan L, Naseri, Take, Viali, Satupa’itea, Nekhai, Sergei, Pankratz, Nathan, Peyser, Patricia A, Taylor, Kent D, Telen, Marilyn J, Wu, Baojun, Yanek, Lisa R, Yang, Ivana V, Albert, Christine, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Bis, Joshua C, Blackwell, Thomas W, Boerwinkle, Eric, Burchard, Esteban G, Carson, April P, Chen, Zhanghua, Chen, Yii-Der Ida, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick T, Fornage, Myriam, Gelb, Bruce D, Gilliland, Frank D, He, Jiang, Islam, Talat, Kaab, Stefan, Kardia, Sharon LR, Kelly, Shannon, Konkle, Barbara A, Kumar, Rajesh, Loos, Ruth JF, Martinez, Fernando D, McGarvey, Stephen T, Meyers, Deborah A, Mitchell, Braxton D, Montgomery, Courtney G, North, Kari E, Palmer, Nicholette D, Peralta, Juan M, Raby, Benjamin A, Redline, Susan, Rich, Stephen S, Roden, Dan, Rotter, Jerome I, Ruczinski, Ingo, Schwartz, David, Sciurba, Frank, Shoemaker, M Benjamin, Silverman, Edwin K, Sinner, Moritz F, Smith, Nicholas L, Smith, Albert V, Tiwari, Hemant K, Vasan, Ramachandran S, Weiss, Scott T, Williams, L Keoki, Zhang, Yingze, Ziv, Elad, Raffield, Laura M, Reiner, Alexander P, Arvanitis, Marios, Greider, Carol W, Mathias, Rasika A, and Battle, Alexis

Subjects
Biological Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Humans, Genome-Wide Association Study, Telomere, K562 Cells, Telomere Homeostasis, Polymorphism, Single Nucleotide, Gene Expression Regulation, CRISPR-Cas Systems, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
Abstract

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Published
2024

2. Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Author

Chen, Fang, Wang, Xingyan, Jang, Seon-Kyeong, Quach, Bryan C, Weissenkampen, J Dylan, Khunsriraksakul, Chachrit, Yang, Lina, Sauteraud, Renan, Albert, Christine M, Allred, Nicholette DD, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Barr, R Graham, Becker, Diane M, Bielak, Lawrence F, Bis, Joshua C, Blangero, John, Boorgula, Meher Preethi, Chasman, Daniel I, Chavan, Sameer, Chen, Yii-Der I, Chuang, Lee-Ming, Correa, Adolfo, Curran, Joanne E, David, Sean P, Fuentes, Lisa de las, Deka, Ranjan, Duggirala, Ravindranath, Faul, Jessica D, Garrett, Melanie E, Gharib, Sina A, Guo, Xiuqing, Hall, Michael E, Hawley, Nicola L, He, Jiang, Hobbs, Brian D, Hokanson, John E, Hsiung, Chao A, Hwang, Shih-Jen, Hyde, Thomas M, Irvin, Marguerite R, Jaffe, Andrew E, Johnson, Eric O, Kaplan, Robert, Kardia, Sharon LR, Kaufman, Joel D, Kelly, Tanika N, Kleinman, Joel E, Kooperberg, Charles, Lee, I-Te, Levy, Daniel, Lutz, Sharon M, Manichaikul, Ani W, Martin, Lisa W, Marx, Olivia, McGarvey, Stephen T, Minster, Ryan L, Moll, Matthew, Moussa, Karine A, Naseri, Take, North, Kari E, Oelsner, Elizabeth C, Peralta, Juan M, Peyser, Patricia A, Psaty, Bruce M, Rafaels, Nicholas, Raffield, Laura M, Reupena, Muagututi’a Sefuiva, Rich, Stephen S, Rotter, Jerome I, Schwartz, David A, Shadyab, Aladdin H, Sheu, Wayne H-H, Sims, Mario, Smith, Jennifer A, Sun, Xiao, Taylor, Kent D, Telen, Marilyn J, Watson, Harold, Weeks, Daniel E, Weir, David R, Yanek, Lisa R, Young, Kendra A, Young, Kristin L, Zhao, Wei, Hancock, Dana B, Jiang, Bibo, Vrieze, Scott, and Liu, Dajiang J

Subjects
Genetics, Tobacco, Drug Abuse (NIDA only), Tobacco Smoke and Health, Substance Misuse, Brain Disorders, Human Genome, Good Health and Well Being, Humans, Transcriptome, Drug Repositioning, Genome-Wide Association Study, Tobacco Use, Biology, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

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

Published
2023

4. Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension

Author

Kelly, Tanika N, Sun, Xiao, He, Karen Y, Brown, Michael R, Taliun, Sarah A Gagliano, Hellwege, Jacklyn N, Irvin, Marguerite R, Mi, Xuenan, Brody, Jennifer A, Franceschini, Nora, Guo, Xiuqing, Hwang, Shih-Jen, de Vries, Paul S, Gao, Yan, Moscati, Arden, Nadkarni, Girish N, Yanek, Lisa R, Elfassy, Tali, Smith, Jennifer A, Chung, Ren-Hua, Beitelshees, Amber L, Patki, Amit, Aslibekyan, Stella, Blobner, Brandon M, Peralta, Juan M, Assimes, Themistocles L, Palmas, Walter R, Liu, Chunyu, Bress, Adam P, Huang, Zhijie, Becker, Lewis C, Hwa, Chii-Min, O’Connell, Jeffrey R, Carlson, Jenna C, Warren, Helen R, Das, Sayantan, Giri, Ayush, Martin, Lisa W, Johnson, W Craig, Fox, Ervin R, Bottinger, Erwin P, Razavi, Alexander C, Vaidya, Dhananjay, Chuang, Lee-Ming, Chang, Yen-Pei C, Naseri, Take, Jain, Deepti, Kang, Hyun Min, Hung, Adriana M, Srinivasasainagendra, Vinodh, Snively, Beverly M, Gu, Dongfeng, Montasser, May E, Reupena, Muagututi A Sefuiva, Heavner, Benjamin D, LeFaive, Jonathon, Hixson, James E, Rice, Kenneth M, Wang, Fei Fei, Nielsen, Jonas B, Huang, Jianfeng, Khan, Alyna T, Zhou, Wei, Nierenberg, Jovia L, Laurie, Cathy C, Armstrong, Nicole D, Shi, Mengyao, Pan, Yang, Stilp, Adrienne M, Emery, Leslie, Wong, Quenna, Hawley, Nicola L, Minster, Ryan L, Curran, Joanne E, Munroe, Patricia B, Weeks, Daniel E, North, Kari E, Tracy, Russell P, Kenny, Eimear E, Shimbo, Daichi, Chakravarti, Aravinda, Rich, Stephen S, Reiner, Alex P, Blangero, John, Redline, Susan, Mitchell, Braxton D, Rao, Dabeeru C, Chen, Yii-Der Ida, Kardia, Sharon LR, Kaplan, Robert C, Mathias, Rasika A, He, Jiang, Psaty, Bruce M, Fornage, Myriam, Loos, Ruth JF, Correa, Adolfo, Boerwinkle, Eric, Rotter, Jerome I, Kooperberg, Charles, and Edwards, Todd L

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Good Health and Well Being, Blood Pressure, Genome-Wide Association Study, Genomics, Humans, Hypertension, Polymorphism, Single Nucleotide, Precision Medicine, allele, blood pressure, genome, hypertension, whole genome sequencing, Samoan Obesity, Lifestyle, and Genetic Adaptations Study (OLaGA) Group, ‡ NHLBI Trans-Omics for Precision Medicine TOPMed) Consortium, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundThe availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.MethodsWe conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.ResultsTwo blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P

Published
2022

5. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Author

Nakao, Tetsushi, Bick, Alexander G, Taub, Margaret A, Zekavat, Seyedeh M, Uddin, Md M, Niroula, Abhishek, Carty, Cara L, Lane, John, Honigberg, Michael C, Weinstock, Joshua S, Pampana, Akhil, Gibson, Christopher J, Griffin, Gabriel K, Clarke, Shoa L, Bhattacharya, Romit, Assimes, Themistocles L, Emery, Leslie S, Stilp, Adrienne M, Wong, Quenna, Broome, Jai, Laurie, Cecelia A, Khan, Alyna T, Smith, Albert V, Blackwell, Thomas W, Codd, Veryan, Nelson, Christopher P, Yoneda, Zachary T, Peralta, Juan M, Bowden, Donald W, Irvin, Marguerite R, Boorgula, Meher, Zhao, Wei, Yanek, Lisa R, Wiggins, Kerri L, Hixson, James E, Gu, C Charles, Peloso, Gina M, Roden, Dan M, Reupena, Muagututi’a S, Hwu, Chii-Min, DeMeo, Dawn L, North, Kari E, Kelly, Shannon, Musani, Solomon K, Bis, Joshua C, Lloyd-Jones, Donald M, Johnsen, Jill M, Preuss, Michael, Tracy, Russell P, Peyser, Patricia A, Qiao, Dandi, Desai, Pinkal, Curran, Joanne E, Freedman, Barry I, Tiwari, Hemant K, Chavan, Sameer, Smith, Jennifer A, Smith, Nicholas L, Kelly, Tanika N, Hidalgo, Bertha, Cupples, L Adrienne, Weeks, Daniel E, Hawley, Nicola L, Minster, Ryan L, Deka, Ranjan, Naseri, Take T, de las Fuentes, Lisa, Raffield, Laura M, Morrison, Alanna C, Vries, Paul S, Ballantyne, Christie M, Kenny, Eimear E, Rich, Stephen S, Whitsel, Eric A, Cho, Michael H, Shoemaker, M Benjamin, Pace, Betty S, Blangero, John, Palmer, Nicholette D, Mitchell, Braxton D, Shuldiner, Alan R, Barnes, Kathleen C, Redline, Susan, Kardia, Sharon LR, Abecasis, Gonçalo R, Becker, Lewis C, Heckbert, Susan R, He, Jiang, Post, Wendy, Arnett, Donna K, Vasan, Ramachandran S, Darbar, Dawood, Weiss, Scott T, McGarvey, Stephen T, de Andrade, Mariza, Chen, Yii-Der Ida, Kaplan, Robert C, Meyers, Deborah A, Custer, Brian S, and Correa, Adolfo

Subjects
Cardiovascular, Genetics, Aging, Heart Disease, Heart Disease - Coronary Heart Disease, Human Genome, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Abstract

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Published
2022

6. Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

Author

DiCorpo, Daniel, Gaynor, Sheila M, Russell, Emily M, Westerman, Kenneth E, Raffield, Laura M, Majarian, Timothy D, Wu, Peitao, Sarnowski, Chloé, Highland, Heather M, Jackson, Anne, Hasbani, Natalie R, de Vries, Paul S, Brody, Jennifer A, Hidalgo, Bertha, Guo, Xiuqing, Perry, James A, O’Connell, Jeffrey R, Lent, Samantha, Montasser, May E, Cade, Brian E, Jain, Deepti, Wang, Heming, D’Oliveira Albanus, Ricardo, Varshney, Arushi, Yanek, Lisa R, Lange, Leslie, Palmer, Nicholette D, Almeida, Marcio, Peralta, Juan M, Aslibekyan, Stella, Baldridge, Abigail S, Bertoni, Alain G, Bielak, Lawrence F, Chen, Chung-Shiuan, Chen, Yii-Der Ida, Choi, Won Jung, Goodarzi, Mark O, Floyd, James S, Irvin, Marguerite R, Kalyani, Rita R, Kelly, Tanika N, Lee, Seonwook, Liu, Ching-Ti, Loesch, Douglas, Manson, JoAnn E, Minster, Ryan L, Naseri, Take, Pankow, James S, Rasmussen-Torvik, Laura J, Reiner, Alexander P, Reupena, Muagututi’a Sefuiva, Selvin, Elizabeth, Smith, Jennifer A, Weeks, Daniel E, Xu, Huichun, Yao, Jie, Zhao, Wei, Parker, Stephen, Alonso, Alvaro, Arnett, Donna K, Blangero, John, Boerwinkle, Eric, Correa, Adolfo, Cupples, L Adrienne, Curran, Joanne E, Duggirala, Ravindranath, He, Jiang, Heckbert, Susan R, Kardia, Sharon LR, Kim, Ryan W, Kooperberg, Charles, Liu, Simin, Mathias, Rasika A, McGarvey, Stephen T, Mitchell, Braxton D, Morrison, Alanna C, Peyser, Patricia A, Psaty, Bruce M, Redline, Susan, Shuldiner, Alan R, Taylor, Kent D, Vasan, Ramachandran S, Viaud-Martinez, Karine A, Florez, Jose C, Wilson, James G, Sladek, Robert, Rich, Stephen S, Rotter, Jerome I, Lin, Xihong, Dupuis, Josée, Meigs, James B, Wessel, Jennifer, and Manning, Alisa K

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Good Health and Well Being, Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States, Biological sciences, Biomedical and clinical sciences
Abstract

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

Published
2022

8. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Author

Natarajan, Pradeep, Pampana, Akhil, Graham, Sarah E, Ruotsalainen, Sanni E, Perry, James A, de Vries, Paul S, Broome, Jai G, Pirruccello, James P, Honigberg, Michael C, Aragam, Krishna, Wolford, Brooke, Brody, Jennifer A, Antonacci-Fulton, Lucinda, Arden, Moscati, Aslibekyan, Stella, Assimes, Themistocles L, Ballantyne, Christie M, Bielak, Lawrence F, Bis, Joshua C, Cade, Brian E, Do, Ron, Doddapaneni, Harsha, Emery, Leslie S, Hung, Yi-Jen, Irvin, Marguerite R, Khan, Alyna T, Lange, Leslie, Lee, Jiwon, Lemaitre, Rozenn N, Martin, Lisa W, Metcalf, Ginger, Montasser, May E, Moon, Jee-Young, Muzny, Donna, O'Connell, Jeffrey R, Palmer, Nicholette D, Peralta, Juan M, Peyser, Patricia A, Stilp, Adrienne M, Tsai, Michael, Wang, Fei Fei, Weeks, Daniel E, Yanek, Lisa R, Wilson, James G, Abecasis, Goncalo, Arnett, Donna K, Becker, Lewis C, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Chang, Yi-Cheng, Chen, Yii-Der I, Choi, Won Jung, Correa, Adolfo, Curran, Joanne E, Daly, Mark J, Dutcher, Susan K, Ellinor, Patrick T, Fornage, Myriam, Freedman, Barry I, Gabriel, Stacey, Germer, Soren, Gibbs, Richard A, He, Jiang, Hveem, Kristian, Jarvik, Gail P, Kaplan, Robert C, Kardia, Sharon LR, Kenny, Eimear, Kim, Ryan W, Kooperberg, Charles, Laurie, Cathy C, Lee, Seonwook, Lloyd-Jones, Don M, Loos, Ruth JF, Lubitz, Steven A, Mathias, Rasika A, Martinez, Karine A Viaud, McGarvey, Stephen T, Mitchell, Braxton D, Nickerson, Deborah A, North, Kari E, Palotie, Aarno, Park, Cheol Joo, Psaty, Bruce M, Rao, DC, Redline, Susan, Reiner, Alexander P, Seo, Daekwan, Seo, Jeong-Sun, Smith, Albert V, Tracy, Russell P, Vasan, Ramachandran S, Kathiresan, Sekar, Cupples, L Adrienne, Rotter, Jerome I, Morrison, Alanna C, Rich, Stephen S, Ripatti, Samuli, and Willer, Cristen

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, FinnGen, Subcutaneous Tissue, Chromosomes, Human, X, Humans, Genetic Predisposition to Disease, Lipids, Eye Proteins, Nerve Tissue Proteins, Gene Expression Regulation, Genotype, Polymorphism, Single Nucleotide, Middle Aged, Female, Male, Genetic Loci, Genetic Association Studies, Whole Genome Sequencing, Phenomics, Cardiometabolic Risk Factors, Chromosomes, Human, X, Polymorphism, Single Nucleotide
Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Published
2021

9. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Author

Nielsen, Jonas B, Rom, Oren, Surakka, Ida, Graham, Sarah E, Zhou, Wei, Roychowdhury, Tanmoy, Fritsche, Lars G, Gagliano Taliun, Sarah A, Sidore, Carlo, Liu, Yuhao, Gabrielsen, Maiken E, Skogholt, Anne Heidi, Wolford, Brooke, Overton, William, Zhao, Ying, Chen, Jin, Zhang, He, Hornsby, Whitney E, Acheampong, Akua, Grooms, Austen, Schaefer, Amanda, Zajac, Gregory JM, Villacorta, Luis, Zhang, Jifeng, Brumpton, Ben, Løset, Mari, Rai, Vivek, Lundegaard, Pia R, Olesen, Morten S, Taylor, Kent D, Palmer, Nicholette D, Chen, Yii-Der, Choi, Seung H, Lubitz, Steven A, Ellinor, Patrick T, Barnes, Kathleen C, Daya, Michelle, Rafaels, Nicholas, Weiss, Scott T, Lasky-Su, Jessica, Tracy, Russell P, Vasan, Ramachandran S, Cupples, L Adrienne, Mathias, Rasika A, Yanek, Lisa R, Becker, Lewis C, Peyser, Patricia A, Bielak, Lawrence F, Smith, Jennifer A, Aslibekyan, Stella, Hidalgo, Bertha A, Arnett, Donna K, Irvin, Marguerite R, Wilson, James G, Musani, Solomon K, Correa, Adolfo, Rich, Stephen S, Guo, Xiuqing, Rotter, Jerome I, Konkle, Barbara A, Johnsen, Jill M, Ashley-Koch, Allison E, Telen, Marilyn J, Sheehan, Vivien A, Blangero, John, Curran, Joanne E, Peralta, Juan M, Montgomery, Courtney, Sheu, Wayne H-H, Chung, Ren-Hua, Schwander, Karen, Nouraie, Seyed M, Gordeuk, Victor R, Zhang, Yingze, Kooperberg, Charles, Reiner, Alexander P, Jackson, Rebecca D, Bleecker, Eugene R, Meyers, Deborah A, Li, Xingnan, Das, Sayantan, Yu, Ketian, LeFaive, Jonathon, Smith, Albert, Blackwell, Tom, Taliun, Daniel, Zollner, Sebastian, Forer, Lukas, Schoenherr, Sebastian, Fuchsberger, Christian, Pandit, Anita, Zawistowski, Matthew, Kheterpal, Sachin, Brummett, Chad M, Natarajan, Pradeep, Schlessinger, David, Lee, Seunggeun, Kang, Hyun Min, Cucca, Francesco, and Holmen, Oddgeir L

Subjects
Liver, Humans, Cardiovascular Diseases, Lipids, Receptors, LDL, Gene Targeting, Gene Silencing, Genome, Human, Biological Specimen Banks, Genome-Wide Association Study, Molecular Targeted Therapy, United Kingdom, Loss of Function Mutation, Phenomics
Abstract

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

Published
2020

10. Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Author

Bick, Alexander G, Weinstock, Joshua S, Nandakumar, Satish K, Fulco, Charles P, Bao, Erik L, Zekavat, Seyedeh M, Szeto, Mindy D, Liao, Xiaotian, Leventhal, Matthew J, Nasser, Joseph, Chang, Kyle, Laurie, Cecelia, Burugula, Bala Bharathi, Gibson, Christopher J, Niroula, Abhishek, Lin, Amy E, Taub, Margaret A, Aguet, Francois, Ardlie, Kristin, Mitchell, Braxton D, Barnes, Kathleen C, Moscati, Arden, Fornage, Myriam, Redline, Susan, Psaty, Bruce M, Silverman, Edwin K, Weiss, Scott T, Palmer, Nicholette D, Vasan, Ramachandran S, Burchard, Esteban G, Kardia, Sharon LR, He, Jiang, Kaplan, Robert C, Smith, Nicholas L, Arnett, Donna K, Schwartz, David A, Correa, Adolfo, de Andrade, Mariza, Guo, Xiuqing, Konkle, Barbara A, Custer, Brian, Peralta, Juan M, Gui, Hongsheng, Meyers, Deborah A, McGarvey, Stephen T, Chen, Ida Yii-Der, Shoemaker, M Benjamin, Peyser, Patricia A, Broome, Jai G, Gogarten, Stephanie M, Wang, Fei Fei, Wong, Quenna, Montasser, May E, Daya, Michelle, Kenny, Eimear E, North, Kari E, Launer, Lenore J, Cade, Brian E, Bis, Joshua C, Cho, Michael H, Lasky-Su, Jessica, Bowden, Donald W, Cupples, L Adrienne, Mak, Angel CY, Becker, Lewis C, Smith, Jennifer A, Kelly, Tanika N, Aslibekyan, Stella, Heckbert, Susan R, Tiwari, Hemant K, Yang, Ivana V, Heit, John A, Lubitz, Steven A, Johnsen, Jill M, Curran, Joanne E, Wenzel, Sally E, Weeks, Daniel E, Rao, Dabeeru C, Darbar, Dawood, Moon, Jee-Young, Tracy, Russell P, Buth, Erin J, Rafaels, Nicholas, Loos, Ruth JF, Durda, Peter, Liu, Yongmei, Hou, Lifang, Lee, Jiwon, Kachroo, Priyadarshini, Freedman, Barry I, Levy, Daniel, Bielak, Lawrence F, Hixson, James E, Floyd, James S, Whitsel, Eric A, Ellinor, Patrick T, Irvin, Marguerite R, Fingerlin, Tasha E, Raffield, Laura M, and Armasu, Sebastian M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biotechnology, Regenerative Medicine, Stem Cell Research, Human Genome, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Cardiovascular, Generic health relevance, Inflammatory and immune system, Good Health and Well Being, Adult, Africa, Aged, Aged, 80 and over, Black People, Cell Self Renewal, Clonal Hematopoiesis, DNA-Binding Proteins, Dioxygenases, Female, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Hematopoietic Stem Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine, Proto-Oncogene Proteins, Tripartite Motif Proteins, United States, Whole Genome Sequencing, alpha Karyopherins, NHLBI Trans-Omics for Precision Medicine Consortium, General Science & Technology
Abstract

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Published
2020

11. Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Author

Li, Xihao, Li, Zilin, Zhou, Hufeng, Gaynor, Sheila M, Liu, Yaowu, Chen, Han, Sun, Ryan, Dey, Rounak, Arnett, Donna K, Aslibekyan, Stella, Ballantyne, Christie M, Bielak, Lawrence F, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Broome, Jai G, Conomos, Matthew P, Correa, Adolfo, Cupples, L Adrienne, Curran, Joanne E, Freedman, Barry I, Guo, Xiuqing, Hindy, George, Irvin, Marguerite R, Kardia, Sharon LR, Kathiresan, Sekar, Khan, Alyna T, Kooperberg, Charles L, Laurie, Cathy C, Liu, X Shirley, Mahaney, Michael C, Manichaikul, Ani W, Martin, Lisa W, Mathias, Rasika A, McGarvey, Stephen T, Mitchell, Braxton D, Montasser, May E, Moore, Jill E, Morrison, Alanna C, O'Connell, Jeffrey R, Palmer, Nicholette D, Pampana, Akhil, Peralta, Juan M, Peyser, Patricia A, Psaty, Bruce M, Redline, Susan, Rice, Kenneth M, Rich, Stephen S, Smith, Jennifer A, Tiwari, Hemant K, Tsai, Michael Y, Vasan, Ramachandran S, Wang, Fei Fei, Weeks, Daniel E, Weng, Zhiping, Wilson, James G, Yanek, Lisa R, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group, Neale, Benjamin M, Sunyaev, Shamil R, Abecasis, Gonçalo R, Rotter, Jerome I, Willer, Cristen J, Peloso, Gina M, Natarajan, Pradeep, and Lin, Xihong

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group, Humans, Genetic Predisposition to Disease, Phenotype, Genome, Models, Genetic, Computer Simulation, Cholesterol, LDL, Genetic Variation, Genome-Wide Association Study, Molecular Sequence Annotation, Whole Genome Sequencing, Models, Genetic, Cholesterol, LDL, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.

Published
2020

12. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sønderby, Ida E, Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P, Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I, Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E, Dale, Anders M, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco JC, de Zubicaray, Greig I, de Zwarte, Sonja MC, Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E, Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C, Grabe, Hans, Groenewold, Nynke A, Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Heinz, Andreas, Hillegers, Manon HJ, Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E, Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A, Jönsson, Erik G, Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma EM, Kolskår, Knut K, Kwok, John B, Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J, Lundervold, Arvid, Martin, Nicholas G, Mather, Karen, Mathias, Samuel R, McCormack, Mark, McMahon, Katie L, McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W, Murray, Robin, Nordvik, Jan E, Nyberg, Lars, Olde Loohuis, Loes M, Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M, Pike, Bruce, and Prieto, Carlos

Subjects
Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, Autism, Biomedical Imaging, Mental Health, Mental health, Adult, Autism Spectrum Disorder, Autistic Disorder, Basal Ganglia, Brain, Chromosome Deletion, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Databases, Factual, Female, Globus Pallidus, Humans, Image Processing, Computer-Assisted, Intellectual Disability, Magnetic Resonance Imaging, Male, Middle Aged, Neurodevelopmental Disorders, Organ Size, Putamen, Schizophrenia, 16p11.2 European Consortium, for the ENIGMA-CNV working group, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P

Published
2020

13. Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Author

Sønderby, Ida E, Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P, Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I, Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E, Dale, Anders M, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco JC, de Zubicaray, Greig I, de Zwarte, Sonja MC, Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E, Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C, Grabe, Hans, Groenewold, Nynke A, Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Heinz, Andreas, Hillegers, Manon HJ, Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E, Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A, Jönsson, Erik G, Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma EM, Kolskår, Knut K, Kwok, John B, Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J, Lundervold, Arvid, Martin, Nicholas G, Mather, Karen, Mathias, Samuel R, McCormack, Mark, McMahon, Katie L, McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W, Murray, Robin, Nordvik, Jan E, Nyberg, Lars, Olde Loohuis, Loes M, Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M, Pike, Bruce, and Prieto, Carlos

Subjects
16p11.2 European Consortium, for the ENIGMA-CNV working group, Neurosciences, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

Published
2020

14. Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

Author

Kowalski, Madeline H, Qian, Huijun, Hou, Ziyi, Rosen, Jonathan D, Tapia, Amanda L, Shan, Yue, Jain, Deepti, Argos, Maria, Arnett, Donna K, Avery, Christy, Barnes, Kathleen C, Becker, Lewis C, Bien, Stephanie A, Bis, Joshua C, Blangero, John, Boerwinkle, Eric, Bowden, Donald W, Buyske, Steve, Cai, Jianwen, Cho, Michael H, Choi, Seung Hoan, Choquet, Hélène, Cupples, L Adrienne, Cushman, Mary, Daya, Michelle, de Vries, Paul S, Ellinor, Patrick T, Faraday, Nauder, Fornage, Myriam, Gabriel, Stacey, Ganesh, Santhi K, Graff, Misa, Gupta, Namrata, He, Jiang, Heckbert, Susan R, Hidalgo, Bertha, Hodonsky, Chani J, Irvin, Marguerite R, Johnson, Andrew D, Jorgenson, Eric, Kaplan, Robert, Kardia, Sharon LR, Kelly, Tanika N, Kooperberg, Charles, Lasky-Su, Jessica A, Loos, Ruth JF, Lubitz, Steven A, Mathias, Rasika A, McHugh, Caitlin P, Montgomery, Courtney, Moon, Jee-Young, Morrison, Alanna C, Palmer, Nicholette D, Pankratz, Nathan, Papanicolaou, George J, Peralta, Juan M, Peyser, Patricia A, Rich, Stephen S, Rotter, Jerome I, Silverman, Edwin K, Smith, Jennifer A, Smith, Nicholas L, Taylor, Kent D, Thornton, Timothy A, Tiwari, Hemant K, Tracy, Russell P, Wang, Tao, Weiss, Scott T, Weng, Lu-Chen, Wiggins, Kerri L, Wilson, James G, Yanek, Lisa R, Zöllner, Sebastian, North, Kari E, Auer, Paul L, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Raffield, Laura M, Reiner, Alexander P, and Li, Yun

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, Humans, Genetic Predisposition to Disease, Computational Biology, Genetics, Population, Gene Frequency, Linkage Disequilibrium, Databases, Genetic, Adult, Aged, Aged, 80 and over, Middle Aged, African Americans, Hispanic Americans, United States, Female, Male, Genome-Wide Association Study, beta-Globins, Genotyping Techniques, Precision Medicine, Whole Genome Sequencing, Genetics, Population, Databases, Genetic, and over, Developmental Biology
Abstract

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Published
2019

15. Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program

Author

Sarnowski, Chloé, Leong, Aaron, Raffield, Laura M, Wu, Peitao, de Vries, Paul S, DiCorpo, Daniel, Guo, Xiuqing, Xu, Huichun, Liu, Yongmei, Zheng, Xiuwen, Hu, Yao, Brody, Jennifer A, Goodarzi, Mark O, Hidalgo, Bertha A, Highland, Heather M, Jain, Deepti, Liu, Ching-Ti, Naik, Rakhi P, O’Connell, Jeffrey R, Perry, James A, Porneala, Bianca C, Selvin, Elizabeth, Wessel, Jennifer, Psaty, Bruce M, Curran, Joanne E, Peralta, Juan M, Blangero, John, Kooperberg, Charles, Mathias, Rasika, Johnson, Andrew D, Reiner, Alexander P, Mitchell, Braxton D, Cupples, L Adrienne, Vasan, Ramachandran S, Correa, Adolfo, Morrison, Alanna C, Boerwinkle, Eric, Rotter, Jerome I, Rich, Stephen S, Manning, Alisa K, Dupuis, Josée, Meigs, James B, Group, TOPMed Diabetes Working, Group, TOPMed Hematology Working, Group, TOPMed Hemostasis Working, and National Heart, Lung

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Prevention, Diabetes, Clinical Research, Metabolic and endocrine, Good Health and Well Being, Cohort Studies, Diabetes Mellitus, Female, Genetic Variation, Glycated Hemoglobin, Humans, Male, Polymorphism, Single Nucleotide, Population Groups, Precision Medicine, TOPMed Diabetes Working Group, TOPMed Hematology Working Group, TOPMed Hemostasis Working Group, National Heart, Lung, and Blood Institute TOPMed Consortium, The Trans-Omics for Precision Medicine (TOPMed) program, hemoglobin A1c, multi-ancestry sample, whole-genome sequence association analyses, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

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

Published
2019

16. The Genetic contribution to solving the cocktail-party problem

Author

Mathias, Samuel R., Knowles, Emma E.M., Mollon, Josephine, Rodrigue, Amanda L., Woolsey, Mary K., Hernandez, Alyssa M., Garrett, Amy S., Fox, Peter T., Olvera, Rene L., Peralta, Juan M., Kumar, Satish, Göring, Harald H.H., Duggirala, Ravi, Curran, Joanne E., Blangero, John, and Glahn, David C.

Published
2022
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17. Rare coding variants in 35 genes associate with circulating lipid levels—A multi-ancestry analysis of 170,000 exomes

Author

Hindy, George, Dornbos, Peter, Chaffin, Mark D., Liu, Dajiang J., Wang, Minxian, Selvaraj, Margaret Sunitha, Zhang, David, Park, Joseph, Aguilar-Salinas, Carlos A., Antonacci-Fulton, Lucinda, Ardissino, Diego, Arnett, Donna K., Aslibekyan, Stella, Atzmon, Gil, Ballantyne, Christie M., Barajas-Olmos, Francisco, Barzilai, Nir, Becker, Lewis C., Bielak, Lawrence F., Bis, Joshua C., Blangero, John, Boerwinkle, Eric, Bonnycastle, Lori L., Bottinger, Erwin, Bowden, Donald W., Bown, Matthew J., Brody, Jennifer A., Broome, Jai G., Burtt, Noël P., Cade, Brian E., Centeno-Cruz, Federico, Chan, Edmund, Chang, Yi-Cheng, Chen, Yii-Der I., Cheng, Ching-Yu, Choi, Won Jung, Chowdhury, Rajiv, Contreras-Cubas, Cecilia, Córdova, Emilio J., Correa, Adolfo, Cupples, L. Adrienne, Curran, Joanne E., Danesh, John, de Vries, Paul S., DeFronzo, Ralph A., Doddapaneni, Harsha, Duggirala, Ravindranath, Dutcher, Susan K., Ellinor, Patrick T., Emery, Leslie S., Florez, Jose C., Fornage, Myriam, Freedman, Barry I., Fuster, Valentin, Garay-Sevilla, Ma. Eugenia, García-Ortiz, Humberto, Germer, Soren, Gibbs, Richard A., Gieger, Christian, Glaser, Benjamin, Gonzalez, Clicerio, Gonzalez-Villalpando, Maria Elena, Graff, Mariaelisa, Graham, Sarah E., Grarup, Niels, Groop, Leif C., Guo, Xiuqing, Gupta, Namrata, Han, Sohee, Hanis, Craig L., Hansen, Torben, He, Jiang, Heard-Costa, Nancy L., Hung, Yi-Jen, Hwang, Mi Yeong, Irvin, Marguerite R., Islas-Andrade, Sergio, Jarvik, Gail P., Kang, Hyun Min, Kardia, Sharon L.R., Kelly, Tanika, Kenny, Eimear E., Khan, Alyna T., Kim, Bong-Jo, Kim, Ryan W., Kim, Young Jin, Koistinen, Heikki A., Kooperberg, Charles, Kuusisto, Johanna, Kwak, Soo Heon, Laakso, Markku, Lange, Leslie A., Lee, Jiwon, Lee, Juyoung, Lee, Seonwook, Lehman, Donna M., Lemaitre, Rozenn N., Linneberg, Allan, Liu, Jianjun, Loos, Ruth J.F., Lubitz, Steven A., Lyssenko, Valeriya, Ma, Ronald C.W., Martin, Lisa Warsinger, Martínez-Hernández, Angélica, Mathias, Rasika A., McGarvey, Stephen T., McPherson, Ruth, Meigs, James B., Meitinger, Thomas, Melander, Olle, Mendoza-Caamal, Elvia, Metcalf, Ginger A., Mi, Xuenan, Mohlke, Karen L., Montasser, May E., Moon, Jee-Young, Moreno-Macías, Hortensia, Morrison, Alanna C., Muzny, Donna M., Nelson, Sarah C., Nilsson, Peter M., O’Connell, Jeffrey R., Orho-Melander, Marju, Orozco, Lorena, Palmer, Colin N.A., Palmer, Nicholette D., Park, Cheol Joo, Park, Kyong Soo, Pedersen, Oluf, Peralta, Juan M., Peyser, Patricia A., Post, Wendy S., Preuss, Michael, Psaty, Bruce M., Qi, Qibin, Rao, D.C., Redline, Susan, Reiner, Alexander P., Revilla-Monsalve, Cristina, Rich, Stephen S., Samani, Nilesh, Schunkert, Heribert, Schurmann, Claudia, Seo, Daekwan, Seo, Jeong-Sun, Sim, Xueling, Sladek, Rob, Small, Kerrin S., So, Wing Yee, Stilp, Adrienne M., Tai, E. Shyong, Tam, Claudia H.T., Taylor, Kent D., Teo, Yik Ying, Thameem, Farook, Tomlinson, Brian, Tsai, Michael Y., Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Teresa, Udler, Miriam S., van Dam, Rob M., Vasan, Ramachandran S., Viaud Martinez, Karine A., Wang, Fei Fei, Wang, Xuzhi, Watkins, Hugh, Weeks, Daniel E., Wilson, James G., Witte, Daniel R., Wong, Tien-Yin, Yanek, Lisa R., Kathiresan, Sekar, Rader, Daniel J., Rotter, Jerome I., Boehnke, Michael, McCarthy, Mark I., Willer, Cristen J., Natarajan, Pradeep, Flannick, Jason A., Khera, Amit V., and Peloso, Gina M.

Published
2022
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19. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

Author

Chu, Audrey Y, Deng, Xuan, Fisher, Virginia A, Drong, Alexander, Zhang, Yang, Feitosa, Mary F, Liu, Ching-Ti, Weeks, Olivia, Choh, Audrey C, Duan, Qing, Dyer, Thomas D, Eicher, John D, Guo, Xiuqing, Heard-Costa, Nancy L, Kacprowski, Tim, Kent, Jack W, Lange, Leslie A, Liu, Xinggang, Lohman, Kurt, Lu, Lingyi, Mahajan, Anubha, O'Connell, Jeffrey R, Parihar, Ankita, Peralta, Juan M, Smith, Albert V, Zhang, Yi, Homuth, Georg, Kissebah, Ahmed H, Kullberg, Joel, Laqua, René, Launer, Lenore J, Nauck, Matthias, Olivier, Michael, Peyser, Patricia A, Terry, James G, Wojczynski, Mary K, Yao, Jie, Bielak, Lawrence F, Blangero, John, Borecki, Ingrid B, Bowden, Donald W, Carr, John Jeffrey, Czerwinski, Stefan A, Ding, Jingzhong, Friedrich, Nele, Gudnason, Vilmunder, Harris, Tamara B, Ingelsson, Erik, Johnson, Andrew D, Kardia, Sharon LR, Langefeld, Carl D, Lind, Lars, Liu, Yongmei, Mitchell, Braxton D, Morris, Andrew P, Mosley, Thomas H, Rotter, Jerome I, Shuldiner, Alan R, Towne, Bradford, Völzke, Henry, Wallaschofski, Henri, Wilson, James G, Allison, Matthew, Lindgren, Cecilia M, Goessling, Wolfram, Cupples, L Adrienne, Steinhauser, Matthew L, and Fox, Caroline S

Subjects
Nutrition, Human Genome, Genetics, Adipocytes, Animals, Body Fat Distribution, Cell Differentiation, Cohort Studies, Ethnicity, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mice, Mice, Inbred C57BL, Obesity, Phenotype, Polymorphism, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.

Published
2017

20. Quantitative HLA‐class‐II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A

Author

Diego, Vincent P., Luu, Bernadette W., Hofmann, Marco, Dinh, Long V., Almeida, Marcio, Powell, Jerry S., Rajalingam, Raja, Peralta, Juan M., Kumar, Satish, Curran, Joanne E., Sauna, Zuben E., Kellerman, Roberta, Park, Yara, Key, Nigel S., Escobar, Miguel A., Huynh, Huy, Verhagen, Anne M., Williams‐Blangero, Sarah, Lehmann, Paul V., Maraskovsky, Eugene, Blangero, John, and Howard, Tom E.

Published
2020
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21. Metabolic syndrome traits exhibit genotype-by-environment interaction in relation to socioeconomic status in the Mexican American family heart study

Author

Diego, Vincent P., primary, Manusov, Eron G., additional, Mao, Xi, additional, Almeida, Marcio, additional, Peralta, Juan M., additional, Curran, Joanne E., additional, Mahaney, Michael C., additional, Göring, Harald, additional, Blangero, John, additional, and Williams-Blangero, Sarah, additional

Published
2024
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23. Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway

Author

Blackburn, Nicholas B., Michael, Laura F., Meikle, Peter J., Peralta, Juan M., Mosior, Marian, McAhren, Scott, Bui, Hai H., Bellinger, Melissa A., Giles, Corey, Kumar, Satish, Leandro, Ana C., Almeida, Marcio, Weir, Jacquelyn M., Mahaney, Michael C., Dyer, Thomas D., Almasy, Laura, VandeBerg, John L., Williams-Blangero, Sarah, Glahn, David C., Duggirala, Ravindranath, Kowala, Mark, Blangero, John, and Curran, Joanne E.

Published
2019
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24. Genotype-by-socioeconomic status interaction influences heart disease risk scores and carotid artery thickness in Mexican Americans: the predominant role of education in comparison to household income and socioeconomic index

Author

Diego, Vincent P., primary, Manusov, Eron G., additional, Mao, Xi, additional, Curran, Joanne E., additional, Göring, Harald, additional, Almeida, Marcio, additional, Mahaney, Michael C., additional, Peralta, Juan M., additional, Blangero, John, additional, and Williams-Blangero, Sarah, additional

Published
2023
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27. Cocktail-party listening and cognitive abilities show strong pleiotropy

Author

Mathias, Samuel R., primary, Knowles, Emma E. M., additional, Mollon, Josephine, additional, Rodrigue, Amanda L., additional, Woolsey, Mary K., additional, Hernandez, Alyssa M., additional, Garret, Amy S., additional, Fox, Peter T., additional, Olvera, Rene L., additional, Peralta, Juan M., additional, Kumar, Satish, additional, Göring, Harald H. H., additional, Duggirala, Ravi, additional, Curran, Joanne E., additional, Blangero, John, additional, and Glahn, David C., additional

Published
2023
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32. Decoding the antioxidant mechanisms underlying arsenic stress in roots of inoculated peanut plants

Author

Ministerio de Ciencia e Innovación (España), European Commission, Ministerio de Educación, Cultura y Deporte (España), Universidad de Granada, Asociación Universitaria Iberoamericana de Postgrado (España), Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Peralta, Juan M., Travaglia, C., Romero-Puertas, María C., Molina-Moya, Eliana, Furlan, A., Castro, S., Bianucci, E., Ministerio de Ciencia e Innovación (España), European Commission, Ministerio de Educación, Cultura y Deporte (España), Universidad de Granada, Asociación Universitaria Iberoamericana de Postgrado (España), Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Peralta, Juan M., Travaglia, C., Romero-Puertas, María C., Molina-Moya, Eliana, Furlan, A., Castro, S., and Bianucci, E.

Abstract

Arsenic (As) has aroused worldwide concern due to its accumulation in the food chain. Inoculated peanut plants with Bradyrhizobium sp. strains showing contrasting tolerance to arsenic (As), were exposed to a low arsenate (As) for 30 days in order to decipher the participation of the antioxidant system, mainly related to glutathione (GSH) metabolism, together with the arsenate reductase (AR) activity in roots. Results showed that the Bradyrhizobium sp. strain modulates differentially the AR activity. An increase in the enzymatic activities of superoxide dismutase, glutathione peroxidase/peroxirredoxin and glutathione S-transferase (GST) was observed, while glutathione reductase (GR) and monodehydroascorbate reductase activities were diminished. Particularly, ascorbate peroxidase (APX) activity was reduced when C-145 was inoculated. Gene expression assays reported an increase in the expression of transcripts GR, cAPX and GST in peanut roots inoculated with SEMIA6144. In the system peanut-Bradyrhizobium sp. C-145, the cAPX expression remained unchanged. In both symbiotic interactions, the total glutathione (GSH) and reduced glutathione (GSH) contents diminished, while oxidized glutathione (GSSG) increased leading to a reduction in the GSH/(GSH + GSSG) ratio. We conclude that, irrespectively of the As tolerance that the inoculated strains shows, the antioxidant response is not strain dependent. Thus, glutathione plays a fundamental role not only as an antioxidant metabolite but also as a key molecule to enhance metalloid detoxification in this inoculated crop. Moreover, as the tripeptide participates in the ROS scavenging, acting mainly as a substrate for GST, allow us to describe its activity as a robust biomarker of arsenic contamination in crops.

Published
2022

35. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Author

Taub, Margaret A., Conomos, Matthew P., Keener, Rebecca, Iyer, Kruthika R., Weinstock, Joshua S., Yanek, Lisa R., Lane, John, Miller-Fleming, Tyne W., Brody, Jennifer A., Raffield, Laura M., McHugh, Caitlin P., Jain, Deepti, Gogarten, Stephanie M., Laurie, Cecelia A., Keramati, Ali, Arvanitis, Marios, Smith, Albert V., Heavner, Benjamin, Barwick, Lucas, Becker, Lewis C., Bis, Joshua C., Blangero, John, Bleecker, Eugene R., Burchard, Esteban G., Celedón, Juan C., Chang, Yen Pei C., Custer, Brian, Darbar, Dawood, de las Fuentes, Lisa, DeMeo, Dawn L., Freedman, Barry I., Garrett, Melanie E., Gladwin, Mark T., Heckbert, Susan R., Hidalgo, Bertha A., Irvin, Marguerite R., Islam, Talat, Johnson, W. Craig, Kaab, Stefan, Launer, Lenore, Lee, Jiwon, Liu, Simin, Moscati, Arden, North, Kari E., Peyser, Patricia A., Rafaels, Nicholas, Seidman, Christine, Weeks, Daniel E., Wen, Fayun, Wheeler, Marsha M., Williams, L. Keoki, Yang, Ivana V., Zhao, Wei, Aslibekyan, Stella, Auer, Paul L., Bowden, Donald W., Cade, Brian E., Chen, Zhanghua, Cho, Michael H., Cupples, L. Adrienne, Curran, Joanne E., Daya, Michelle, Deka, Ranjan, Eng, Celeste, Fingerlin, Tasha E., Guo, Xiuqing, Hou, Lifang, Hwang, Shih-Jen, Johnsen, Jill M., Kenny, Eimear E., Levin, Albert M., Liu, Chunyu, Minster, Ryan L., Naseri, Take, Nouraie, Mehdi, Reupena, Muagututi‘a Sefuiva, Sabino, Ester C., Smith, Jennifer A., Smith, Nicholas L., Lasky-Su, Jessica, Taylor, James G., VI, Telen, Marilyn J., Tiwari, Hemant K., Tracy, Russell P., White, Marquitta J., Zhang, Yingze, Wiggins, Kerri L., Weiss, Scott T., Vasan, Ramachandran S., Taylor, Kent D., Sinner, Moritz F., Silverman, Edwin K., Shoemaker, M. Benjamin, Sheu, Wayne H.-H., Sciurba, Frank, Schwartz, David A., Rotter, Jerome I., Roden, Daniel, Redline, Susan, Raby, Benjamin A., Psaty, Bruce M., Peralta, Juan M., Palmer, Nicholette D., Nekhai, Sergei, Montgomery, Courtney G., Mitchell, Braxton D., Meyers, Deborah A., McGarvey, Stephen T., Mak, Angel C.Y., Loos, Ruth J.F., Kumar, Rajesh, Kooperberg, Charles, Konkle, Barbara A., Kelly, Shannon, Kardia, Sharon L.R., Kaplan, Robert, He, Jiang, Gui, Hongsheng, Gilliland, Frank D., Gelb, Bruce D., Fornage, Myriam, Ellinor, Patrick T., de Andrade, Mariza, Correa, Adolfo, Chen, Yii-Der Ida, Boerwinkle, Eric, Barnes, Kathleen C., Ashley-Koch, Allison E., Arnett, Donna K., Albert, Christine, Laurie, Cathy C., Abecasis, Goncalo, Nickerson, Deborah A., Wilson, James G., Rich, Stephen S., Levy, Daniel, Ruczinski, Ingo, Aviv, Abraham, Blackwell, Thomas W., Thornton, Timothy, O’Connell, Jeff, Cox, Nancy J., Perry, James A., Armanios, Mary, Battle, Alexis, Pankratz, Nathan, Reiner, Alexander P., and Mathias, Rasika A.

Published
2022
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38. The G505A Nonsynonymous Single-Nucleotide Polymorphism (SNP) in TAFI, the Gene Encoding Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Is Pleiotropically Associated with TAFI Antigen Levels and Coronary Heart Disease (CHD) in Mexican Americans of South Texas

Author

Jhaveri, Shuchita, primary, Diego, Vincent P., additional, Nguyen, Hoang Anh Thi, additional, Kumar, Satish, additional, Almeida, Marcio A., additional, Peralta, Juan M, additional, Curran, Joanne E., additional, Luu, Bernadette W., additional, Lehman, Donna M., additional, DeFronzo, Ralph A, additional, Escobar, Miguel A., additional, Williams-Blangero, Sarah, additional, Duggirala, Ravi, additional, Powell, Jerry S., additional, Almasy, Laura, additional, Blangero, John, additional, and Howard, Tom E., additional

Published
2021
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39. The Factor II (FII) Expression Quantitative Trait Locus (eQTL) Prothrombin G20210A Is Pleiotropically Associated with Plasma Fibrinogen Levels and Has a Profound Effect on Obesity in Mexican Americans of South Texas

Author

Nguyen, Hoang Anh Thi, primary, Diego, Vincent P., additional, Jhaveri, Shuchita, additional, Almeida, Marcio A., additional, Kumar, Satish, additional, Peralta, Juan M, additional, Curran, Joanne E., additional, Luu, Bernadette W., additional, Lehman, Donna M., additional, DeFronzo, Ralph A, additional, Escobar, Miguel A., additional, Williams-Blangero, Sarah, additional, Duggirala, Ravi, additional, Powell, Jerry S., additional, Almasy, Laura, additional, Blangero, John, additional, and Howard, Tom E., additional

Published
2021
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41. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Walters, G Bragi, Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas B., Blangero, John, Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Cahn, Wiepke, Calhoun, Vince D., Caspers, Svenja, Ching, Christopher R K, Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J C, de Zubicaray, Greig I., de Zwarte, Sonja M C, Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Ge, Tian, Glahn, David C., Grabe, Hans J., Groenewold, Nynke A., Gústafsson, Ómar, Haavik, Jan, Haberg, Asta K., Hall, Jeremy, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Hibar, Derrek P., Hillegers, Manon H J, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E M, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E J, Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Modenato, Claudia, Sánchez, Jennifer Monereo, Morris, Derek W., Mühleisen, Thomas W., Murray, Robin M., Nielsen, Jacob, Nordvik, Jan E., Nyberg, Lars, Loohuis, Loes M Olde, Ophoff, Roel A., Owen, Michael J., Paus, Tomas, Pausova, Zdenka, Peralta, Juan M., Pike, G Bruce, Prieto, Carlos, Quinlan, Erin B., Reinbold, Céline S, Marques, Tiago Reis, Rucker, James J H, Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., van 't Ent, Dennis, van den Bree, Marianne B M, Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Wright, Margaret J., Agartz, Ingrid, Djurovic, Srdjan, Westlye, Lars T., Stefansson, Hreinn, Stefansson, Kari, Jacquemont, Sébastien, Thompson, Paul M., Andreassen, Ole A., Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Walters, G Bragi, Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas B., Blangero, John, Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Cahn, Wiepke, Calhoun, Vince D., Caspers, Svenja, Ching, Christopher R K, Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J C, de Zubicaray, Greig I., de Zwarte, Sonja M C, Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Ge, Tian, Glahn, David C., Grabe, Hans J., Groenewold, Nynke A., Gústafsson, Ómar, Haavik, Jan, Haberg, Asta K., Hall, Jeremy, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Hibar, Derrek P., Hillegers, Manon H J, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E M, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E J, Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Modenato, Claudia, Sánchez, Jennifer Monereo, Morris, Derek W., Mühleisen, Thomas W., Murray, Robin M., Nielsen, Jacob, Nordvik, Jan E., Nyberg, Lars, Loohuis, Loes M Olde, Ophoff, Roel A., Owen, Michael J., Paus, Tomas, Pausova, Zdenka, Peralta, Juan M., Pike, G Bruce, Prieto, Carlos, Quinlan, Erin B., Reinbold, Céline S, Marques, Tiago Reis, Rucker, James J H, Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., van 't Ent, Dennis, van den Bree, Marianne B M, Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Wright, Margaret J., Agartz, Ingrid, Djurovic, Srdjan, Westlye, Lars T., Stefansson, Hreinn, Stefansson, Kari, Jacquemont, Sébastien, Thompson, Paul M., and Andreassen, Ole A.

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021
Full Text
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42. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Nyberg, Lars, Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, and Nyberg, Lars

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021

43. Results from an Association-Scan of the Extended MHC-Class-II Region Using Novel Association-Based Statistical Methods Establish That DQ Allotypes and Race Independently Influence the Risk of Factor VIII Inhibitor Development in Hemophilia-A Patients

Author

Ibarra, Paola, Almeida, Marcio A., Diego, Vincent P., Luu, Bernadette W., Viel, Kevin R., Rajalingam, Raja, Ameri, Afshin, Chitlur, Meera, Kim, Benjamin, Castillo, Grecia, Powell, Jerry S., Peralta, Juan M., Escobar, Miguel A., Williams-Blangero, Sarah, Blangero, John, Kasper, Carol K., Almasy, Laura, and Howard, Tom E.

Published
2023
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44. Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion in ANGPTL3

Author

Blackburn, Nicholas B., primary, Meikle, Peter J., additional, Peralta, Juan M., additional, Kumar, Satish, additional, Leandro, Ana C., additional, Bellinger, Melissa A., additional, Giles, Corey, additional, Huynh, Kevin, additional, Mahaney, Michael C., additional, Göring, Harald H.H., additional, VandeBerg, John L., additional, Williams-Blangero, Sarah, additional, Glahn, David C., additional, Duggirala, Ravindranath, additional, Blangero, John, additional, Michael, Laura F., additional, and Curran, Joanne E., additional

Published
2021
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46. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sonderby, Ida E., Gustafsson, Omar, Doan, Nhat Trung, Hibar, Derrek P., Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret, I, Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M., Buelow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J. C., de Zubicaray, Greig, I, de Zwarte, Sonja M. C., Delanty, Norman, den Braber, Anouk, Desrivieres, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E., Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C., Grabe, Hans, Groenewold, Nynke A., Haavik, Jan, Haberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Heinz, Andreas, Hillegers, Manon H. J., Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A., Joensson, Erik G., Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma E. M., Kolskar, Knut K., Kwok, John B., Le Hellard, Stephanie, Leu, Costin, Liu, Jingyu, Lundervold, Astri J., Lundervold, Arvid, Martin, Nicholas G., Mather, Karen, Mathias, Samuel R., McCormack, Mark, McMahon, Katie L., McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Muehleisen, Thomas W., Murray, Robin, Nordvik, Jan E., Nyberg, Lars, Loohuis, Loes M. Olde, Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M., Pike, Bruce, Prieto, Carlos, Pudas, Sara, Quinlan, Erin, Quintana, Daniel S., Reinbold, Celine S., Marques, Tiago Reis, Reymond, Alexandre, Richard, Genevieve, Rodriguez-Herreros, Borja, Roiz-Santianez, Roberto, Rokicki, Jarek, Rucker, James, Sachdev, Perminder, Sanders, Anne-Marthe, Sando, Sigrid B., Schmaal, Lianne, Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Sisodiya, Sanjay, Steen, Vidar M., Stein, Dan J., Steinberg, Stacy, Strike, Lachlan, Teumer, Alexander, Thalamuthu, Anbu, Tordesillas-Gutierrez, Diana, Turner, Jessica, Ueland, Torill, Uhlmann, Anne, Ulfarsson, Magnus O., van't Ent, Dennis, van der Meer, Dennis, van Haren, Neeltje E. M., Vaskinn, Anja, Vassos, Evangelos, Walters, G. Bragi, Wang, Yunpeng, Wen, Wei, Whelan, Christopher D., Wittfeld, Katharina, Wright, Margie, Yamamori, Hidenaga, Zayats, Tetyana, Agartz, Ingrid, Westlye, Lars T., Jacquemont, Sebastien, Djurovic, Srdjan, Stefansson, Hreinn, Stefansson, Kari, Thompson, Paul, Andreassen, Ole A., Sonderby, Ida E., Gustafsson, Omar, Doan, Nhat Trung, Hibar, Derrek P., Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret, I, Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M., Buelow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J. C., de Zubicaray, Greig, I, de Zwarte, Sonja M. C., Delanty, Norman, den Braber, Anouk, Desrivieres, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E., Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C., Grabe, Hans, Groenewold, Nynke A., Haavik, Jan, Haberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Heinz, Andreas, Hillegers, Manon H. J., Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A., Joensson, Erik G., Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma E. M., Kolskar, Knut K., Kwok, John B., Le Hellard, Stephanie, Leu, Costin, Liu, Jingyu, Lundervold, Astri J., Lundervold, Arvid, Martin, Nicholas G., Mather, Karen, Mathias, Samuel R., McCormack, Mark, McMahon, Katie L., McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Muehleisen, Thomas W., Murray, Robin, Nordvik, Jan E., Nyberg, Lars, Loohuis, Loes M. Olde, Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M., Pike, Bruce, Prieto, Carlos, Pudas, Sara, Quinlan, Erin, Quintana, Daniel S., Reinbold, Celine S., Marques, Tiago Reis, Reymond, Alexandre, Richard, Genevieve, Rodriguez-Herreros, Borja, Roiz-Santianez, Roberto, Rokicki, Jarek, Rucker, James, Sachdev, Perminder, Sanders, Anne-Marthe, Sando, Sigrid B., Schmaal, Lianne, Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Sisodiya, Sanjay, Steen, Vidar M., Stein, Dan J., Steinberg, Stacy, Strike, Lachlan, Teumer, Alexander, Thalamuthu, Anbu, Tordesillas-Gutierrez, Diana, Turner, Jessica, Ueland, Torill, Uhlmann, Anne, Ulfarsson, Magnus O., van't Ent, Dennis, van der Meer, Dennis, van Haren, Neeltje E. M., Vaskinn, Anja, Vassos, Evangelos, Walters, G. Bragi, Wang, Yunpeng, Wen, Wei, Whelan, Christopher D., Wittfeld, Katharina, Wright, Margie, Yamamori, Hidenaga, Zayats, Tetyana, Agartz, Ingrid, Westlye, Lars T., Jacquemont, Sebastien, Djurovic, Srdjan, Stefansson, Hreinn, Stefansson, Kari, Thompson, Paul, and Andreassen, Ole A.

Abstract

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes., Correction: Sønderby, I.E., Gústafsson, Ó., Doan, N.T. et al. Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia. Mol Psychiatry 25, 692–695 (2020). https://doi.org/10.1038/s41380-019-0358-8

Published
2020
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47. Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Author

van der Meer, Dennis, Sønderby, Ida E, Kaufmann, Tobias, Walters, G Bragi, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas B, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Cahn, Wiepke, Calhoun, Vince D, Caspers, Svenja, Cavalleri, Gianpiero L, Ching, Christopher R K, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J C, de Zubicaray, Greig I, de Zwarte, Sonja M C, Delanty, Norman, den Braber, Anouk, Desrivieres, Sylvane, Di Forti, Marta, Doherty, Joanne L, Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon E, Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C, Grabe, Hans J, Groenewold, Nynke A, Gústafsson, Ómar, Haavik, Jan, Haberg, Asta K, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Hibar, Derrek P, Hillegers, Manon H J, Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E, Ikeda, Masashi, Jacquemont, Sébastien, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G, Kikuchi, Masataka, Knowles, Emma E M, Kwok, John B, Le Hellard, Stephanie, Linden, David E J, Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri J, Martin, Nicholas G, Mather, Karen A, Mathias, Samuel R, McMahon, Katie L, McRae, Allan F, Medland, Sarah E, Moberget, Torgeir, Moreau, Clara, Morris, Derek W, Mühleisen, Thomas W, Murray, Robin M, Nordvik, Jan E, Nyberg, Lars, Olde Loohuis, Loes M, Ophoff, Roel A, Owen, Michael J, Paus, Tomas, Pausova, Zdenka, Peralta, Juan M, Pike, Bruce, Prieto, Carlos, Quinlan, Erin Burke, Reinbold, Céline S, Reis Marques, Tiago, Rucker, James J H, Sachdev, Perminder S, Sando, Sigrid B, Schofield, Peter R, Schork, Andrew J, Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Silva, Ana I, Sisodiya, Sanjay M, Steen, Vidar M, Stein, Dan J, Strike, Lachlan T, Tamnes, Christian K, Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Úlfarsson, Magnús Ö, van 't Ent, Dennis, van den Bree, Marianne B M, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Wright, Margaret J, Zayats, Tetyana, Dale, Anders M, Djurovic, Srdjan, Agartz, Ingrid, Westlye, Lars T, Stefánsson, Hreinn, Stefánsson, Kári, Thompson, Paul M, Andreassen, Ole A, van der Meer, Dennis, Sønderby, Ida E, Kaufmann, Tobias, Walters, G Bragi, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas B, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Cahn, Wiepke, Calhoun, Vince D, Caspers, Svenja, Cavalleri, Gianpiero L, Ching, Christopher R K, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J C, de Zubicaray, Greig I, de Zwarte, Sonja M C, Delanty, Norman, den Braber, Anouk, Desrivieres, Sylvane, Di Forti, Marta, Doherty, Joanne L, Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon E, Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C, Grabe, Hans J, Groenewold, Nynke A, Gústafsson, Ómar, Haavik, Jan, Haberg, Asta K, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Hibar, Derrek P, Hillegers, Manon H J, Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E, Ikeda, Masashi, Jacquemont, Sébastien, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G, Kikuchi, Masataka, Knowles, Emma E M, Kwok, John B, Le Hellard, Stephanie, Linden, David E J, Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri J, Martin, Nicholas G, Mather, Karen A, Mathias, Samuel R, McMahon, Katie L, McRae, Allan F, Medland, Sarah E, Moberget, Torgeir, Moreau, Clara, Morris, Derek W, Mühleisen, Thomas W, Murray, Robin M, Nordvik, Jan E, Nyberg, Lars, Olde Loohuis, Loes M, Ophoff, Roel A, Owen, Michael J, Paus, Tomas, Pausova, Zdenka, Peralta, Juan M, Pike, Bruce, Prieto, Carlos, Quinlan, Erin Burke, Reinbold, Céline S, Reis Marques, Tiago, Rucker, James J H, Sachdev, Perminder S, Sando, Sigrid B, Schofield, Peter R, Schork, Andrew J, Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Silva, Ana I, Sisodiya, Sanjay M, Steen, Vidar M, Stein, Dan J, Strike, Lachlan T, Tamnes, Christian K, Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Úlfarsson, Magnús Ö, van 't Ent, Dennis, van den Bree, Marianne B M, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Wright, Margaret J, Zayats, Tetyana, Dale, Anders M, Djurovic, Srdjan, Agartz, Ingrid, Westlye, Lars T, Stefánsson, Hreinn, Stefánsson, Kári, Thompson, Paul M, and Andreassen, Ole A

Abstract

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cog

Published
2020
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48. Correction : Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia (Molecular Psychiatry, (2020), 25, 3, (584-602), 10.1038/s41380-018-0118-1)

Author

Sønderby, Ida E., Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P., Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I., Bralten, Janita, Brattbak, Hans Richard, Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J.C., de Zubicaray, Greig I., de Zwarte, Sonja M.C., Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E., Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C., Grabe, Hans, Groenewold, Nynke A., Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Heinz, Andreas, Hillegers, Manon H.J., Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke Jan, Hulshoff, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A., Jönsson, Erik G., Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma E.M., Kolskår, Knut K., Kwok, John B., Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J., Lundervold, Arvid, Martin, Nicholas G., Mather, Karen, Mathias, Samuel R., McCormack, Mark, McMahon, Katie L., McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W., Murray, Robin, Nordvik, Jan E., Nyberg, Lars, Olde Loohuis, Loes M., Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M., Pike, Bruce, Prieto, Carlos, Pudas, Sara, Quinlan, Erin, Quintana, Daniel S., Reinbold, Céline S., Marques, Tiago Reis, Reymond, Alexandre, Richard, Genevieve, Rodriguez-Herreros, Borja, Roiz-Santiañez, Roberto, Rokicki, Jarek, Rucker, James, Sachdev, Perminder, Sanders, Anne Marthe, Sando, Sigrid B., Schmaal, Lianne, Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Sisodiya, Sanjay, Steen, Vidar M., Stein, Dan J., Steinberg, Stacy, Strike, Lachlan, Teumer, Alexander, Thalamuthu, Anbu, Tordesillas-Gutierrez, Diana, Turner, Jessica, Ueland, Torill, Uhlmann, Anne, Ulfarsson, Magnus O., van 't Ent, Dennis, van der Meer, Dennis, van Haren, Neeltje E.M., Vaskinn, Anja, Vassos, Evangelos, Walters, G. Bragi, Wang, Yunpeng, Wen, Wei, Whelan, Christopher D., Wittfeld, Katharina, Wright, Margie, Yamamori, Hidenaga, Zayats, Tetyana, Agartz, Ingrid, Westlye, Lars T., Jacquemont, Sébastien, Djurovic, Srdjan, Stefánsson, Hreinn, Stefánsson, Kári, Thompson, Paul, Andreassen, Ole A., other, and, Sønderby, Ida E., Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P., Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I., Bralten, Janita, Brattbak, Hans Richard, Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J.C., de Zubicaray, Greig I., de Zwarte, Sonja M.C., Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E., Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C., Grabe, Hans, Groenewold, Nynke A., Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Heinz, Andreas, Hillegers, Manon H.J., Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke Jan, Hulshoff, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A., Jönsson, Erik G., Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma E.M., Kolskår, Knut K., Kwok, John B., Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J., Lundervold, Arvid, Martin, Nicholas G., Mather, Karen, Mathias, Samuel R., McCormack, Mark, McMahon, Katie L., McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W., Murray, Robin, Nordvik, Jan E., Nyberg, Lars, Olde Loohuis, Loes M., Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M., Pike, Bruce, Prieto, Carlos, Pudas, Sara, Quinlan, Erin, Quintana, Daniel S., Reinbold, Céline S., Marques, Tiago Reis, Reymond, Alexandre, Richard, Genevieve, Rodriguez-Herreros, Borja, Roiz-Santiañez, Roberto, Rokicki, Jarek, Rucker, James, Sachdev, Perminder, Sanders, Anne Marthe, Sando, Sigrid B., Schmaal, Lianne, Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Sisodiya, Sanjay, Steen, Vidar M., Stein, Dan J., Steinberg, Stacy, Strike, Lachlan, Teumer, Alexander, Thalamuthu, Anbu, Tordesillas-Gutierrez, Diana, Turner, Jessica, Ueland, Torill, Uhlmann, Anne, Ulfarsson, Magnus O., van 't Ent, Dennis, van der Meer, Dennis, van Haren, Neeltje E.M., Vaskinn, Anja, Vassos, Evangelos, Walters, G. Bragi, Wang, Yunpeng, Wen, Wei, Whelan, Christopher D., Wittfeld, Katharina, Wright, Margie, Yamamori, Hidenaga, Zayats, Tetyana, Agartz, Ingrid, Westlye, Lars T., Jacquemont, Sébastien, Djurovic, Srdjan, Stefánsson, Hreinn, Stefánsson, Kári, Thompson, Paul, Andreassen, Ole A., and other, and

Abstract

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

Published
2020

50. Transcriptomic Profiling of Fibropapillomatosis in Green Sea Turtles (Chelonia mydas) From South Texas

Author

Blackburn, Nicholas B., primary, Leandro, Ana Cristina, additional, Nahvi, Nina, additional, Devlin, Mariana A., additional, Leandro, Marcelo, additional, Martinez Escobedo, Ignacio, additional, Peralta, Juan M., additional, George, Jeff, additional, Stacy, Brian A., additional, deMaar, Thomas W., additional, Blangero, John, additional, Keniry, Megan, additional, and Curran, Joanne E., additional

Published
2021
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