Jeffrey Robert Gruen MD

Professor of Pediatrics (Neonatology), Genetics, and Investigative Medicine

Research Interests

Genetics of communication disorders and learning disabilities, dyslexia, language impairment (LI); Biological underpinnings of dyslexia, language impairment, learning disabilities, communication disorders

Current Projects

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.


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.

Extensive Research Description



Selected Publications

  • Eicher 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 Jr, Dale AM, Jernigan TL, Pourcain BS, Smith GD, Ring SM, Gruen JR; for the Pediatric Imaging, Neurocognition Genetics Study. Genome-Wide Association Study of Shared Components of Reading Disability and Language Impairment. Genes Brain Behav. 2013 Sep 11. doi: 10.1111/gbb.12085. [Epub ahead of print] PMID: 24024963 [PubMed - as supplied by publisher]
  • Eicher JD, and Gruen JR. Imaging-Genetics in Dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments. Molecular Genetics and Metabolism 2013 (http://dx.doi.org/10.1016/j.ymgme.2013.07.001, in press).
  • *Powers 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 Jul 11;93(1):19-28. PMID: 23746548 [PubMed - in process] PMCID: PMC3710765 [Available on 2014/1/11]. *Recipient of the 2013 AJHG Cotterman Award, for the paper that best represents outstanding scientific contributions to the field of human genetics from a pre- or post-doctoral trainee.
  • Eicher 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 May 15;8(5):e63762. PMID: 23691092 PMCID: PMC3655151.
  • Cho K, Frijters JC, Zhang H, Miller LL, Gruen JR. Prenatal exposure to nicotine and impaired reading performance. J Pediatr. 2013 Apr;162(4):713-718.e2. PMID: 23122624.
  • Marino C, Meng H, Mascheretti S, Rusconi M, Cope N, Giorda, R Molteni M, and Gruen JR. DCDC2 genetic variants and susceptibility to developmental dyslexia. Psychiatric Genetics, 2012 22(1):25-30 PMID: 21881542
  • Meng H, Powers NR, Tang L, Cope NA, Zhang P-X, Fuleihan R, Gibson C, Page GP, Gruen JR. A dyslexia-associated variant in DCDC2 changes gene expression. Behavior Genetics 2011 Jan;41(1):58-66 PMID: 21042874
  • Zhang H, Liu L, Wang X, Gruen JR. (2007). Guideline for data analysis of genomewide association studies. Cancer Genomics Proteomics. 4(1):27-34. Review. PMID: 17726238
  • Cope 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 Jun 7;63(1):148-156. [Epub ahead of print] PMID: 22750057.
  • * Meng 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. (2005). DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc Natl Acad Sci U S A. 22102(47):17053-8. PMID: 16278297

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