Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes.

Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis-eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non-pain disorders.

[1]  A. Hofman,et al.  Genome-wide association study of migraine implicates a common susceptibility variant on 8 q 22 . 1 , 2010 .

[2]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[3]  P. Visscher,et al.  Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets , 2016, Nature Genetics.

[4]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[5]  Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder , 2011, BMC Medical Genetics.

[6]  Andrey A. Shabalin,et al.  Matrix eQTL: ultra fast eQTL analysis via large matrix operations , 2011, Bioinform..

[7]  G. Schütz,et al.  Guanylate Binding Protein 1–Mediated Interaction of T Cell Antigen Receptor Signaling with the Cytoskeleton , 2014, The Journal of Immunology.

[8]  Blair H. Smith,et al.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region , 2012, Annals of the rheumatic diseases.

[9]  Hyunsoo Kim,et al.  Alternative transcription exceeds alternative splicing in generating the transcriptome diversity of cerebellar development. , 2011, Genome research.

[10]  A. Singleton,et al.  Genomewide association studies and human disease. , 2009, The New England journal of medicine.

[11]  N. Lau,et al.  The coming of age for Piwi proteins. , 2007, Molecular cell.

[12]  J. Marchini,et al.  Fast and accurate genotype imputation in genome-wide association studies through pre-phasing , 2012, Nature Genetics.

[13]  W. Maixner,et al.  The phenotypic and genetic signatures of common musculoskeletal pain conditions , 2013, Nature Reviews Rheumatology.

[14]  Qian Wang,et al.  Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS , 2015, Human Genetics.

[15]  Charles M Perou,et al.  Evaluating the comparability of gene expression in blood and brain , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[16]  Wolfgang Hoffmann,et al.  Genome-wide association study reveals three susceptibility loci for common migraine in the general population , 2011, Nature Genetics.

[17]  Joel Hirschhorn,et al.  SNPsnap: a Web-based tool for identification and annotation of matched SNPs , 2015, Bioinform..

[18]  J. Sanes,et al.  Lineage of neurons and glia in chick dorsal root ganglia: analysis in vivo with a recombinant retrovirus. , 1991, Development.

[19]  E. Airoldi,et al.  Accounting for Experimental Noise Reveals That mRNA Levels, Amplified by Post-Transcriptional Processes, Largely Determine Steady-State Protein Levels in Yeast , 2014, bioRxiv.

[20]  William Maixner,et al.  Orofacial pain prospective evaluation and risk assessment study--the OPPERA study. , 2011, The journal of pain : official journal of the American Pain Society.

[21]  Sergei Egorov,et al.  Pathway studio - the analysis and navigation of molecular networks , 2003, Bioinform..

[22]  W. Maixner,et al.  A pain research agenda for the 21st century. , 2014, The journal of pain : official journal of the American Pain Society.

[23]  Rafael A. Irizarry,et al.  A framework for oligonucleotide microarray preprocessing , 2010, Bioinform..

[24]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[25]  Loren J. Martin,et al.  The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors , 2015, Science Translational Medicine.

[26]  J. Jacobs,et al.  Vascular leakage in the dorsal root ganglia of the rat, studied with horseradish peroxidase , 1976, Journal of the Neurological Sciences.

[27]  Eric Bair,et al.  Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. , 2011, The journal of pain : official journal of the American Pain Society.

[28]  L. Liang,et al.  Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation , 2015, PloS one.

[29]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[30]  C. Benoist,et al.  Mice lacking all conventional MHC class II genes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Linnarsson,et al.  Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing , 2014, Nature Neuroscience.

[32]  Thomas Meitinger,et al.  Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1 , 2010, Nature Genetics.

[33]  Ramnik J. Xavier,et al.  Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor. , 2010, Blood.

[34]  Peggy Hall,et al.  The NHGRI GWAS Catalog, a curated resource of SNP-trait associations , 2013, Nucleic Acids Res..

[35]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[36]  D. Zaykin,et al.  Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia. , 2012, Arthritis and rheumatism.

[37]  Ross M. Fraser,et al.  A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness , 2014, PLoS genetics.

[38]  S. Ludwig,et al.  A new splice variant of the human guanylate‐binding protein 3 mediates anti‐influenza activity through inhibition of viral transcription and replication , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[40]  S. Wahl,et al.  Genome-wide association study of acute post-surgical pain in humans. , 2009, Pharmacogenomics.

[41]  Clifford J. Woolf,et al.  Nociceptors—Noxious Stimulus Detectors , 2007, Neuron.

[42]  Shi-xun Wu,et al.  Association between Caspase-9 promoter region polymorphisms and discogenic low back pain , 2011, Connective tissue research.

[43]  H. Hakonarson,et al.  TAOK3, a novel genome-wide association study locus associated with morphine requirement and postoperative pain in a retrospective pediatric day surgery population , 2014, PAIN®.

[44]  J. Buxbaum,et al.  A SPECTRAL APPROACH INTEGRATING FUNCTIONAL GENOMIC ANNOTATIONS FOR CODING AND NONCODING VARIANTS , 2015, Nature Genetics.

[45]  H. Stockinger,et al.  Gamma Interferon-Induced Guanylate Binding Protein 1 Is a Novel Actin Cytoskeleton Remodeling Factor , 2013, Molecular and Cellular Biology.

[46]  M. Gratacós,et al.  Genome-wide analysis of single nucleotide polymorphisms and copy number variants in fibromyalgia suggest a role for the central nervous system , 2014, PAIN®.