Zuber V.,Institute of Clinical Medicine |
Zuber V.,University of Oslo |
Zuber V.,European Bioinformatics Institute |
Marconett C.N.,University of Southern California |
And 45 more authors.
Journal of the National Cancer Institute | Year: 2016
Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10-6) and blood triglycerides (P = 1.39x10-5). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40-10-4) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21, Pcombined = 5.20x10-9). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer. © The Author 2016. Published by Oxford University Press. All rights reserved.
Andreassen O.A.,University of Oslo |
McEvoy L.K.,Multimodal Imaging Laboratory |
McEvoy L.K.,University of California at San Diego |
Wang Y.,University of Oslo |
And 16 more authors.
Hypertension | Year: 2014
Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. Epidemiological studies suggest associations between blood pressure and several diseases and traits, which may partly arise from a shared genetic basis (genetic pleiotropy). Using genome-wide association studies summary statistics and a genetic pleiotropy-informed conditional false discovery rate method, we systematically investigated genetic overlap between systolic blood pressure (SBP) and 12 comorbid traits and diseases. We found significant enrichment of single nucleotide polymorphisms associated with SBP as a function of their association with body mass index, low-density lipoprotein, waist/hip ratio, schizophrenia, bone mineral density, type 1 diabetes mellitus, and celiac disease. In contrast, the magnitude of enrichment due to shared polygenic effects was smaller with the other phenotypes (triglycerides, high-density lipoproteins, type 2 diabetes mellitus, rheumatoid arthritis, and height). Applying the conditional false discovery rate method to the enriched phenotypes, we identified 62 loci associated with SBP (false discovery rate <0.01), including 42 novel loci. The observed polygenic overlap between SBP and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors but also reflect an etiologic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in SBP. © 2014 American Heart Association, Inc.
Eicher J.D.,Yale University |
Powers N.R.,Yale University |
Miller L.L.,University of Bristol |
Akshoomoff N.,Center for Human Development |
And 32 more authors.
Genes, Brain and Behavior | Year: 2013
Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR=1.81, P=5.45×10-7) and COL4A2 (OR=1.71, P=7.59×10-7). Markers within NDST4 showed the strongest associations with LI individually (OR=1.827, P=1.40×10-7). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P=0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language. © 2013 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.
Chan A.M.,Medical Engineering and Medical Physics |
Dykstra A.R.,Harvard-MIT Division of Health Sciences and Technology |
Jayaram V.,Harvard University |
Leonard M.K.,Multimodal Imaging Laboratory |
And 5 more authors.
Cerebral cortex (New York, N.Y. : 1991) | Year: 2014
How the brain extracts words from auditory signals is an unanswered question. We recorded approximately 150 single and multi-units from the left anterior superior temporal gyrus of a patient during multiple auditory experiments. Against low background activity, 45% of units robustly fired to particular spoken words with little or no response to pure tones, noise-vocoded speech, or environmental sounds. Many units were tuned to complex but specific sets of phonemes, which were influenced by local context but invariant to speaker, and suppressed during self-produced speech. The firing of several units to specific visual letters was correlated with their response to the corresponding auditory phonemes, providing the first direct neural evidence for phonological recoding during reading. Maximal decoding of individual phonemes and words identities was attained using firing rates from approximately 5 neurons within 200 ms after word onset. Thus, neurons in human superior temporal gyrus use sparse spatially organized population encoding of complex acoustic-phonetic features to help recognize auditory and visual words. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: email@example.com.
Ferjan Ramirez N.,Multimodal Imaging Laboratory |
Leonard M.K.,Multimodal Imaging Laboratory |
Torres C.,Multimodal Imaging Laboratory |
Halgren E.,University of California at San Diego
Cerebral cortex (New York, N.Y. : 1991) | Year: 2014
The relation between the timing of language input and development of neural organization for language processing in adulthood has been difficult to tease apart because language is ubiquitous in the environment of nearly all infants. However, within the congenitally deaf population are individuals who do not experience language until after early childhood. Here, we investigated the neural underpinnings of American Sign Language (ASL) in 2 adolescents who had no sustained language input until they were approximately 14 years old. Using anatomically constrained magnetoencephalography, we found that recently learned signed words mainly activated right superior parietal, anterior occipital, and dorsolateral prefrontal areas in these 2 individuals. This spatiotemporal activity pattern was significantly different from the left fronto-temporal pattern observed in young deaf adults who acquired ASL from birth, and from that of hearing young adults learning ASL as a second language for a similar length of time as the cases. These results provide direct evidence that the timing of language experience over human development affects the organization of neural language processing. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org.
PubMed | University of California at San Diego, University of California at San Francisco, University of Washington and Multimodal Imaging Laboratory
Type: Case Reports | Journal: Cerebral cortex (New York, N.Y. : 1991) | Year: 2016
One key question in neurolinguistics is the extent to which the neural processing system for language requires linguistic experience during early life to develop fully. We conducted a longitudinal anatomically constrained magnetoencephalography (aMEG) analysis of lexico-semantic processing in 2 deaf adolescents who had no sustained language input until 14 years of age, when they became fully immersed in American Sign Language. After 2 to 3 years of language, the adolescents neural responses to signed words were highly atypical, localizing mainly to right dorsal frontoparietal regions and often responding more strongly to semantically primed words (Ferjan Ramirez N, Leonard MK, Torres C, Hatrak M, Halgren E, Mayberry RI. 2014. Neural language processing in adolescent first-language learners. Cereb Cortex. 24 (10): 2772-2783). Here, we show that after an additional 15 months of language experience, the adolescents neural responses remained atypical in terms of polarity. While their responses to less familiar signed words still showed atypical localization patterns, the localization of responses to highly familiar signed words became more concentrated in the left perisylvian language network. Our findings suggest that the timing of language experience affects the organization of neural language processing; however, even in adolescence, language representation in the human brain continues to evolve with experience.
White N.S.,University of California at San Diego |
White N.S.,Multimodal Imaging Laboratory |
Dale A.M.,University of California at San Diego
Magnetic Resonance in Medicine | Year: 2014
Purpose: While many recent studies have demonstrated improved detection and characterization of malignant lesions using high b-value diffusion imaging techniques, little is known about the underlying physical characteristics of tumor cells that modulate the restricted water signal at high b on clinical scanners.Methods: Monte Carlo simulations of diffusion in a synthetic tumor cell environment were used to study the specific effects of tumor cell diameter and nuclear volume fraction (m) on high b diffusion contrast.Results: Results indicate that clinical pulsed-gradient spinecho diffusion-weighted signals measured at high b (Δ4000 s/ mm2), long diffusion time (Δ ∼40-60 ms), and long echo time (TE ∼60-140 ms) are generally insensitive to tumor cell diameter, but increase exponentially with m. Moreover, these results are predicted by a simple analytic expression for the intracellular restricted water signal with elevated T2 for the intranuclear versus cytosolic compartment.Conclusion: Nuclear volume fraction is an important characteristic of cancer cells that modulates the apparent restriction of water at high b on clinical scanners. This model offers a possible explanation for the apparent unreliable correlation between tumor cell density (cellularity) and traditional ADC. © 2013 Wiley Periodicals, Inc.