Jeffrey R Gruen, MD
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Research Summary
Our primary research interest is in finding and characterizing genes that cause reading disability, commonly known as dyslexia. Reading disability is present in 10 to 20% of school children and is the most common cause of learning disability. It is also mostly genetic in origin with genetic factors accounting for 40 to 60% of the poor performance in reading tests. Through genetic studies of families and children with reading disability we identified a major contributor, called doublecortin-domain- containing-2 (DCDC2) We found that a deletion in a putative regulatory sequence in DCDC2 is present in ~20% of dyslexics. We have found 14 variations (alleles) of this regulatory (enhancer) sequence and are identifying which alleles are the most deleterious, which may be protective, and how these variations functionally alter brain development. We are also assessing dyslexia using various imaging modalities in children - including functional magnetic resonance imaging (fMRI) and resting state connectivity – as an endophenotype for conditioning our genetic studies (“imaging-genetics”). Our preliminary data suggest that imaging is a sensitive phenotype for dyslexia and will identify new functional-genetic units for reading not previously appreciated.
Speciailzed Terms: Genetics of communication disorders and learning disabilities, dyslexia, and language impairment (LI); Biological underpinnings of dyslexia, language impairment, learning disabilities, and communication disorders.
Extensive Research Description
Projects
Human Genetic Studies: We use human genetic methods such as genetic association and sequencing studies to identify specific genes and genetic elements that contribute to dyslexia and language impairment. Methods range from specific interrogation of the DYX2 risk locus on chromosome 6p22 with a dense marker panel, to hypothesis-free methods such as genome-wide association and sequencing studies. We have collaborated with groups across the country and internationally to ascertain and collect subjects. Ongoing collaborations include the Avon Longitudinal Study of Parents and Children (ALSPAC) at the University of Bristol (UK), the Colorado Learning Disabilities Research Center at the University of Colorado-Boulder, The Child Language Research Center at the University of Iowa, Case Western Reserve University, as well as numerous other national and international collaborators. Our goal for these studies is to identify genetic elements that substantially contribute to reading- and language-related processes in order to (1) gain valuable insight into the mechanisms underlying dyslexia and language impairment—and also into the mechanisms underlying the biology of normal reading and language—and (2) attempt to use genetic information to identify children that may be at risk for communication disorders, in order to apply early intervention and improve the outcome for these individuals.
Molecular Genetic Studies: Our human genetic studies have recently uncovered a synergistic genetic interaction between two risk elements within the DYX2 locus: (1) READ1 (‘regulatory element associated with dyslexia 1’) within intron 2 of DCDC2 and (2) a risk haplotype within KIAA0319, another known dyslexia risk gene in the same locus as DCDC2. Using shift assays, mass spectrometry, and chromatin immunoprecipitation techniques, we determined that the potent transcription factor ETV6 specifically binds the READ1 element. Ongoing studies aim to determine the biological implications of READ1 and its possible regulatory capabilities, within DYX2 and throughout the genome. Future studies are planned to study the biological effects of READ1 alleles in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) that can be differentiated into neural progenitor cells and terminally differentiated neural cells. .
The Yale Genes, Reading and Dyslexia (GRaD) Study: The GRaD Study is a multi-center case/control study of the genetics of dyslexia in Hispanic-American and African-American children. Each child receives an extensive battery of standardized reading, language, IQ, attention, and motivation assessments. We collect DNA from every child in preparation for a genome-wide association study (GWAS) to identify genetic markers informative in understudied populations in the U.S. and Canada. To date we have enrolled over 1100 children from recruitment and testing centers in New Haven, Boston, Toronto, Denver, Boulder, Albuquerque, and Baltimore.
Imaging Genetics (IG): In addition to traditional cognitive assessments, we also perform genetic association with non-invasive brain imaging phenotypes, using magnetic resonance imaging (MRI). We use several MRI protocols, including structural (T2 and diffusion weighted imaging), functional, structural connectivity (fractional anisotropy), and functional connectivity. Subjects for these studies are recruited from the Pediatric Imaging NeuroGenetics (PING) Study, as well as the GRaD Study. The goal of these imaging-genetics studies is to connect risk variants from our neurobehavioral genetic studies to the biological phenotypes observed with high-resolution structural and functional imaging.
Sluggish Cognitive Tempo (SCT): This is a collaborative project with investigators at The Kennedy-Krieger Institute at Johns Hopkins University in Baltimore. The aim of this project is to examine the relationships between neuropsychological skills and candidate gene variants in children ages 8 to 15 years who display slow processing speed in the context of behaviorally defined sluggish cognitive tempo (SCT). [I1] SCT is a collection of symptoms characterized by lethargy, under activity, and slowness, and has been observed in a variety of childhood conditions including attention deficit hyperactivity disorder (ADHD) and dyslexia. SCT and processing speed are considered overlapping yet distinct constructs. Children with ADHD commonly display slowed processing speed; however, slow processing speed is also sometimes observed in dyslexia. Therefore, processing speed and components of SCT may account, in part, for the comorbidity between ADHD and dyslexia.
[I1]I would move this to the end of the paragraph.
Coauthors
Research Interests
Dyslexia; Genetics; Language; Language Development Disorders; Learning Disabilities; Investigative Techniques; Neonatology; Pediatrics
Selected Publications
- Discovery of 42 genome-wide significant loci associated with dyslexiaDoust C, Fontanillas P, Eising E, Gordon SD, Wang Z, Alagöz G, Molz B, Pourcain B, Francks C, Marioni R, Zhao J, Paracchini S, Talcott J, Monaco A, Stein J, Gruen J, Olson R, Willcutt E, DeFries J, Pennington B, Smith S, Wright M, Martin N, Auton A, Bates T, Fisher S, Luciano M. Discovery of 42 genome-wide significant loci associated with dyslexia Nature Genetics 2022, 54: 1621-1629. PMID: 36266505, PMCID: PMC9649434, DOI: 10.1038/s41588-022-01192-y.
- Orthographic Depth May Influence the Degree of Severity of Maze Learning Performance in Children at Risk for Reading DisorderGabel L, Battison A, Truong D, Lindström E, Voss K, Yu Y, Roongruengratanakul S, Shyntassov K, Riebesell S, Toumanios N, Nielsen-Pheiffer C, Paniagua S, Gruen J. Orthographic Depth May Influence the Degree of Severity of Maze Learning Performance in Children at Risk for Reading Disorder Developmental Neuroscience 2022, 44: 651-670. PMID: 36223729, PMCID: PMC9928771, DOI: 10.1159/000527480.
- 7 The Genetics of Disorders Affecting the Premature NewbornProsnitz A, Gruen J, Bhandari V. 7 The Genetics of Disorders Affecting the Premature Newborn 2022, 149-185. DOI: 10.1016/b978-0-12-815236-2.00006-0.
- Enrichment of putatively damaging rare variants in the DYX2 locus and the reading-related genes CCDC136 and FLNCAdams AK, Smith SD, Truong DT, Willcutt EG, Olson RK, DeFries JC, Pennington BF, Gruen JR. Enrichment of putatively damaging rare variants in the DYX2 locus and the reading-related genes CCDC136 and FLNC Human Genetics 2017, 136: 1395-1405. PMID: 28866788, PMCID: PMC5702371, DOI: 10.1007/s00439-017-1838-z.
- Reading‐Related Causal Attributions for Success and Failure: Dynamic Links With Reading SkillFrijters JC, Tsujimoto KC, Boada R, Gottwald S, Hill D, Jacobson LA, Lovett MW, Mahone EM, Willcutt EG, Wolf M, Bosson‐Heenan J, Gruen JR. Reading‐Related Causal Attributions for Success and Failure: Dynamic Links With Reading Skill Reading Research Quarterly 2017, 53: 127-148. PMID: 29391653, PMCID: PMC5788039, DOI: 10.1002/rrq.189.
- Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disordersTruong DT, Shriberg LD, Smith SD, Chapman KL, Scheer-Cohen AR, DeMille MM, Adams AK, Nato AQ, Wijsman EM, Eicher JD, Gruen JR. Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders Human Genetics 2016, 135: 1329-1341. PMID: 27535846, PMCID: PMC5065602, DOI: 10.1007/s00439-016-1717-z.
- Executive Functions Contribute Uniquely to Reading Competence in Minority YouthJacobson LA, Koriakin T, Lipkin P, Boada R, Frijters JC, Lovett MW, Hill D, Willcutt E, Gottwald S, Wolf M, Bosson-Heenan J, Gruen JR, Mahone EM. Executive Functions Contribute Uniquely to Reading Competence in Minority Youth Journal Of Learning Disabilities 2016, 50: 422-433. PMID: 26755569, PMCID: PMC5960349, DOI: 10.1177/0022219415618501.
- Alleles of a Polymorphic ETV6 Binding Site in DCDC2 Confer Risk of Reading and Language ImpairmentPowers N, Eicher J, Butter F, Kong Y, Miller L, Ring S, Mann M, Gruen J. Alleles of a Polymorphic ETV6 Binding Site in DCDC2 Confer Risk of Reading and Language Impairment American Journal Of Human Genetics 2014, 94: 798. PMCID: PMC4067563, DOI: 10.1016/j.ajhg.2014.04.001.
- Iron Metabolism and Related DisordersHoda K, Bowlus C, Chu T, Gruen J. Iron Metabolism and Related Disorders 2014 DOI: 10.1016/b978-0-12-801238-3.05573-2.
- The Genetics of Disorders Affecting the Premature NewbornProsnitz A, Gruen J, Bhandari V. The Genetics of Disorders Affecting the Premature Newborn 2014 DOI: 10.1016/b978-0-12-801238-3.05514-8.
- Genome‐wide association study of shared components of reading disability and language impairmentEicher JD, Powers NR, Miller LL, Akshoomoff N, Amaral DG, Bloss CS, Libiger O, Schork NJ, Darst BF, Casey BJ, Chang L, Ernst T, Frazier J, Kaufmann WE, Keating B, Kenet T, Kennedy D, Mostofsky S, Murray SS, Sowell ER, Bartsch H, Kuperman JM, Brown TT, Hagler DJ, Dale AM, Jernigan TL, St. Pourcain B, Smith G, Ring SM, Gruen JR, for the Pediatric Imaging N. Genome‐wide association study of shared components of reading disability and language impairment Genes Brain & Behavior 2013, 12: 792-801. PMID: 24024963, PMCID: PMC3904347, DOI: 10.1111/gbb.12085.
- Imaging-genetics in dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairmentsEicher JD, Gruen JR. Imaging-genetics in dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments Molecular Genetics And Metabolism 2013, 110: 201-212. PMID: 23916419, PMCID: PMC3800223, DOI: 10.1016/j.ymgme.2013.07.001.
- Alleles of a Polymorphic ETV6 Binding Site in DCDC2 Confer Risk of Reading and Language ImpairmentPowers NR, Eicher JD, Butter F, Kong Y, Miller LL, Ring SM, Mann M, Gruen JR. Alleles of a Polymorphic ETV6 Binding Site in DCDC2 Confer Risk of Reading and Language Impairment American Journal Of Human Genetics 2013, 93: 19-28. PMID: 23746548, PMCID: PMC3710765, DOI: 10.1016/j.ajhg.2013.05.008.
- Associations of Prenatal Nicotine Exposure and the Dopamine Related Genes ANKK1 and DRD2 to Verbal LanguageEicher JD, Powers NR, Cho K, Miller LL, Mueller KL, Ring SM, Tomblin JB, Gruen JR. Associations of Prenatal Nicotine Exposure and the Dopamine Related Genes ANKK1 and DRD2 to Verbal Language PLOS ONE 2013, 8: e63762. PMID: 23691092, PMCID: PMC3655151, DOI: 10.1371/journal.pone.0063762.
- Genome‐wide association studies of severe communication processes and affectation of multiple prevalent pediatric communication disordersEicher J, Powers N, Gruen J. Genome‐wide association studies of severe communication processes and affectation of multiple prevalent pediatric communication disorders The FASEB Journal 2013, 27: 533.5-533.5. DOI: 10.1096/fasebj.27.1_supplement.533.5.
- Chapter 101 Iron Metabolism and Related DisordersHoda K, Bowlus C, Chu T, Gruen J. Chapter 101 Iron Metabolism and Related Disorders 2013, 1-41. DOI: 10.1016/b978-0-12-383834-6.00106-3.
- Chapter 41 The Genetics of Disorders Affecting the Premature NewbornProsnitz A, Gruen J, Bhandari V. Chapter 41 The Genetics of Disorders Affecting the Premature Newborn 2013, 1-22. DOI: 10.1016/b978-0-12-383834-6.00171-3.
- Prenatal Exposure to Nicotine and Impaired Reading PerformanceCho K, Frijters JC, Zhang H, Miller LL, Gruen JR. Prenatal Exposure to Nicotine and Impaired Reading Performance The Journal Of Pediatrics 2012, 162: 713-718.e2. PMID: 23122624, PMCID: PMC3577994, DOI: 10.1016/j.jpeds.2012.09.041.
- Variants in the DYX2 locus are associated with altered brain activation in reading-related brain regions in subjects with reading disabilityCope N, Eicher JD, Meng H, Gibson CJ, Hager K, Lacadie C, Fulbright RK, Constable RT, Page GP, Gruen JR. Variants in the DYX2 locus are associated with altered brain activation in reading-related brain regions in subjects with reading disability NeuroImage 2012, 63: 148-156. PMID: 22750057, PMCID: PMC3518451, DOI: 10.1016/j.neuroimage.2012.06.037.
- DCDC2 genetic variants and susceptibility to developmental dyslexiaMarino C, Meng H, Mascheretti S, Rusconi M, Cope N, Giorda R, Molteni M, Gruen JR. DCDC2 genetic variants and susceptibility to developmental dyslexia Psychiatric Genetics 2012, 22: 25-30. PMID: 21881542, PMCID: PMC3232293, DOI: 10.1097/ypg.0b013e32834acdb2.
- A Highly Sensitive, High-Throughput Assay for the Detection of Turner SyndromeRivkees S, Hager K, Hosono S, Wise A, Li P, Rinder H, Gruen J. A Highly Sensitive, High-Throughput Assay for the Detection of Turner Syndrome Obstetrical & Gynecological Survey 2011, 66: 421-422. DOI: 10.1097/ogx.0b013e3182338c32.
- A Dyslexia-Associated Variant in DCDC2 Changes Gene ExpressionMeng H, Powers NR, Tang L, Cope NA, Zhang PX, Fuleihan R, Gibson C, Page GP, Gruen JR. A Dyslexia-Associated Variant in DCDC2 Changes Gene Expression Behavior Genetics 2010, 41: 58-66. PMID: 21042874, PMCID: PMC3053575, DOI: 10.1007/s10519-010-9408-3.
- The Genomics of Bronchopulmonary DysplasiaBhandari V, Gruen J. The Genomics of Bronchopulmonary Dysplasia NeoReviews 2007, 8: e336-e344. DOI: 10.1542/neo.8-8-e336.
- Genetic susceptibility to retinopathy of prematurityBizzarro M, Hussain N, Jonsson B, Feng R, Ment L, Gruen J, Zhang H, Bhandari V. Genetic susceptibility to retinopathy of prematurity American Journal Of Ophthalmology 2007, 143: 375-376. DOI: 10.1016/j.ajo.2006.12.016.
- Genetic approaches to complications of prematurity.Meng H, Gruen JR. Genetic approaches to complications of prematurity. Frontiers In Bioscience-Landmark 2007, 12: 2344-51. PMID: 17127244, DOI: 10.2741/2236.
- Guideline for data analysis of genomewide association studies.Zhang H, Liu L, Wang X, Gruen JR. Guideline for data analysis of genomewide association studies. Cancer Genomics & Proteomics 2007, 4: 27-34. PMID: 17726238.
- Genetic Polymorphisms of Hemostasis Genes and Primary Outcome of Very Low Birth Weight Infants Härtel C, König I, Köster S, et al (Univ at Lübeck, Germany; Kinderklinik auf der Bult, Hannover, Germany; Olgahospital, Stuttgart, Germany; et al) Pediatrics 118:683–689, 2006§Gruen J. Genetic Polymorphisms of Hemostasis Genes and Primary Outcome of Very Low Birth Weight Infants Härtel C, König I, Köster S, et al (Univ at Lübeck, Germany; Kinderklinik auf der Bult, Hannover, Germany; Olgahospital, Stuttgart, Germany; et al) Pediatrics 118:683–689, 2006§ Yearbook Of Neonatal And Perinatal Medicine 2007, 2007: 63-65. DOI: 10.1016/s8756-5005(08)70041-6.
- Is There a Genetic Susceptibility to Bronchopulmonary Dysplasia?Shetty A, Gruen J, Bhandari V. Is There a Genetic Susceptibility to Bronchopulmonary Dysplasia? Current Respiratory Medicine Reviews 2006, 2: 253-262. DOI: 10.2174/157339806778018935.
- DCDC2 is associated with reading disability and modulates neuronal development in the brainMeng H, Smith SD, Hager K, Held M, Liu J, Olson RK, Pennington BF, DeFries JC, Gelernter J, O'Reilly-Pol T, Somlo S, Skudlarski P, Shaywitz SE, Shaywitz BA, Marchione K, Wang Y, Paramasivam M, LoTurco JJ, Page GP, Gruen JR. DCDC2 is associated with reading disability and modulates neuronal development in the brain Proceedings Of The National Academy Of Sciences Of The United States Of America 2005, 102: 17053-17058. PMID: 16278297, PMCID: PMC1278934, DOI: 10.1073/pnas.0508591102.
- Peaks of Linkage Are Localized by a BAC/PAC Contig of the 6p Reading Disability LocusAhn J, Won T, Zia A, Reutter H, Kaplan D, Sparks R, Gruen J. Peaks of Linkage Are Localized by a BAC/PAC Contig of the 6p Reading Disability Locus Genomics 2001, 78: 19-29. PMID: 11707069, DOI: 10.1006/geno.2001.6645.
- Human GABAB receptor 1 gene: Eight novel sequence variantsHisama F, Gruen J, Choi J, Huseinovic M, Grigorenko E, Pauls D, Mattson R, Gelernter J, Wood F, Goei V. Human GABAB receptor 1 gene: Eight novel sequence variants Human Mutation 2001, 17: 349-350. PMID: 11295833, DOI: 10.1002/humu.34.
- Identification of polymorphisms in the GABAB receptor gene and linkage study of attention‐deficit hyperactivity disorderBarr C, Feng Y, Wigg K, Roberts W, Malone M, Schachar R, Tannock R, Gruen J, Goei V, Kennedy J. Identification of polymorphisms in the GABAB receptor gene and linkage study of attention‐deficit hyperactivity disorder International Journal Of Genomics 2000, 1: 194-201. DOI: 10.1002/1438-826x(200012)1:5/6<194::aid-gnfd194>3.0.co;2-2.
- Identification of polymorphisms in theGABAB receptor gene and linkage study of attention-deficit hyperactivity disorderBarr C, Feng Y, Wigg K, Roberts W, Malone M, Schachar R, Tannock R, Gruen J, Goei V, Kennedy J. Identification of polymorphisms in theGABAB receptor gene and linkage study of attention-deficit hyperactivity disorder International Journal Of Genomics 2000, 1: 1-8. DOI: 10.1002/(sici)1438-826x(200012)1:5/6<1::aid-gnfd4>3.0.co;2-8.
- Localization, allelic heterogeneity, and origins of the hemochromatosis geneRaha-Chowdhury R, Gruen J. Localization, allelic heterogeneity, and origins of the hemochromatosis gene 2000, 75-90. DOI: 10.1017/cbo9780511666476.008.
- Cloning of a Novel MHC-Encoded Serine Peptidase Highly Expressed by Cortical Epithelial Cells of the ThymusBowlus C, Ahn J, Chu T, Gruen J. Cloning of a Novel MHC-Encoded Serine Peptidase Highly Expressed by Cortical Epithelial Cells of the Thymus Cellular Immunology 1999, 196: 80-86. PMID: 10527559, DOI: 10.1006/cimm.1999.1543.
- The genomic organization of the histone clusters on human 6p21.3Ahn J, Gruen J. The genomic organization of the histone clusters on human 6p21.3 Mammalian Genome 1999, 10: 768-770. PMID: 10384058, DOI: 10.1007/s003359901089.
- Human gamma-aminobutyric acid B receptor gene: complementary DNA cloning, expression, chromosomal location, and genomic organizationGoei V, Choi J, Ahn J, Bowlus C, Raha-Chowdhury R, Gruen J. Human gamma-aminobutyric acid B receptor gene: complementary DNA cloning, expression, chromosomal location, and genomic organization Biological Psychiatry 1998, 44: 659-666. PMID: 9798068, DOI: 10.1016/s0006-3223(98)00244-3.
- Evolving Views of the Major Histocompatibility ComplexGruen J, Weissman S. Evolving Views of the Major Histocompatibility Complex Blood 1997, 90: 4252-4265. PMID: 9373235, DOI: 10.1182/blood.v90.11.4252.
- Evolving Views of the Major Histocompatibility ComplexGruen J, Weissman S. Evolving Views of the Major Histocompatibility Complex Blood 1997, 90: 4252-4265. DOI: 10.1182/blood.v90.11.4252.4252_4252_4265.
- Haplotype Analysis of Hemochromatosis: Evaluation of Different Linkage-Disequilibrium Approaches and Evolution of Disease ChromosomesAjioka R, Jorde L, Gruen J, Yu P, Dimitrova D, Barrow J, Radisky E, Edwards C, Griffen L, Kushner J. Haplotype Analysis of Hemochromatosis: Evaluation of Different Linkage-Disequilibrium Approaches and Evolution of Disease Chromosomes American Journal Of Human Genetics 1997, 60: 1439-1447. PMID: 9199565, PMCID: PMC1716127, DOI: 10.1086/515466.
- O338 A transcription map of the Major Histocompatibility Complex (MHC) Class I regionWeissman S, Nalabolu S, Chu T, Bowles C, Fan W, Goei V, Wei H, Sivakamasundari R, Liu Y, Xu H, Parimoo S, Nallur G, Ajioka R, Shukla H, Bray-Ward P, Pan J, Nallur G, Gruen J. O338 A transcription map of the Major Histocompatibility Complex (MHC) Class I region Human Immunology 1996, 47: 64. DOI: 10.1016/0198-8859(96)85033-6.
- Cloning of a New "Finger" Protein Gene (ZNF173) within the Class I Region of the Human MHCChu T, Capossela A, Coleman R, Goei V, Nallur G, Gruen J. Cloning of a New "Finger" Protein Gene (ZNF173) within the Class I Region of the Human MHC Genomics 1995, 29: 229-239. PMID: 8530076, DOI: 10.1006/geno.1995.1236.
- Physical and genetic mapping of the telomeric major histocompatibility complex region in man and relevance to the primary hemochromatosis gene (HFE)Gruen J, Goei V, Summers K, Capossela A, Powell L, Halliday J, Zoghbi H, Shukla H, Weissman S. Physical and genetic mapping of the telomeric major histocompatibility complex region in man and relevance to the primary hemochromatosis gene (HFE) Genomics 1992, 14: 232-240. PMID: 1427838, DOI: 10.1016/s0888-7543(05)80211-3.
- Differential expression of novel Gsα signal transduction protein cDNA speciesSwaroop A, Agarwal N, Gruen J, Bick D, Weissman S. Differential expression of novel Gsα signal transduction protein cDNA species Nucleic Acids Research 1991, 19: 4725-4729. PMID: 1716359, PMCID: PMC328715, DOI: 10.1093/nar/19.17.4725.