{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:52:50Z","timestamp":1787579570323,"version":"build-2736575974"},"reference-count":106,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The genetic mechanisms of childhood development in its many facets remain largely undeciphered. In the population of healthy infants studied in the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) program, we have identified a range of dependencies among the observed phenotypes of fetal and early childhood growth, neurological development, and a number of genetic variants. We have quantified these dependencies using our information theory-based methods. The genetic variants show dependencies with single phenotypes as well as pleiotropic effects on more than one phenotype and thereby point to a large number of brain-specific and brain-expressed gene candidates. These dependencies provide a basis for connecting a range of variants with a spectrum of phenotypes (pleiotropy) as well as with each other. A broad survey of known regulatory expression characteristics, and other function-related information from the literature for these sets of candidate genes allowed us to assemble an integrated body of evidence, including a partial regulatory network, that points towards the biological basis of these general dependencies. Notable among the implicated loci are RAB11FIP4 (next to NF1), MTMR7 and PLD5, all highly expressed in the brain; DNMT1 (DNA methyl transferase), highly expressed in the placenta; and PPP1R12B and DMD (dystrophin), known to be important growth and development genes. While we cannot specify and decipher the mechanisms responsible for the phenotypes in this study, a number of connections for further investigation of fetal and early childhood growth and neurological development are indicated. These results and this approach open the door to new explorations of early human development.<\/jats:p>","DOI":"10.1371\/journal.pone.0242684","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T19:13:43Z","timestamp":1607022823000},"page":"e0242684","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Complex genetic dependencies among growth and neurological phenotypes in healthy children: Towards deciphering developmental mechanisms"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8215-6938","authenticated-orcid":true,"given":"Lisa","family":"Uechi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahjoubeh","family":"Jalali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayson D.","family":"Wilbur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9649-169X","authenticated-orcid":true,"given":"Jonathan L.","family":"French","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. 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Albers","year":"2006","edition":"3"},{"issue":"1","key":"pone.0242684.ref017","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1097\/00001648-199001000-00010","article-title":"No adjustments are needed for multiple comparisons","volume":"1","author":"KJ Rothman","year":"1990","journal-title":"Epidemiology"},{"key":"pone.0242684.ref018","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1136\/bmj.316.7139.1236","article-title":"What\u2019s wrong with Bonferroni adjustments","volume":"315","author":"TV Perneger","year":"1998","journal-title":"BMJ"},{"key":"pone.0242684.ref019","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1471-2288-2-8","article-title":"Do multiple outcome measures require p-value adjustment?","volume":"2","author":"RJ Feise","year":"2002","journal-title":"BMC Med Res Methodol"},{"key":"pone.0242684.ref020","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1016\/j.athoracsur.2015.11.024","article-title":"Adjust for Multiple Comparisons? It\u2019s Not That Simple","volume":"101","author":"AD Althouse","year":"2016","journal-title":"Ann Thorac Surg"},{"key":"pone.0242684.ref021","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/gepi.20310","article-title":"A Multiple Testing Correction Method for Genetic Association Studies Using Correlated Single Nucleotide Polymorphisms","volume":"32","author":"X Gao","year":"2008","journal-title":"Genetic Epidemiology"},{"issue":"1","key":"pone.0242684.ref022","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/gepi.20430","article-title":"Avoiding the high Bonferroni penalty in genome-wide association studies","volume":"34","author":"X Gao","year":"2010","journal-title":"Genet Epidemiol"},{"key":"pone.0242684.ref023","doi-asserted-by":"crossref","first-page":"e70174","DOI":"10.1371\/journal.pone.0070174","article-title":"A Possible Mechanism behind Autoimmune Disorders Discovered By Genome-Wide Linkage and Association Analysis in Celiac 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Amlie-Wolf","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pone.0242684.ref030","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1126\/science.1222794","article-title":"Systematic localization of common disease-associated variation in regulatory DNA","volume":"337","author":"MT Maurano","year":"2012","journal-title":"Science"},{"key":"pone.0242684.ref031","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1101\/gr.137323.112","article-title":"Annotation of functional variation in personal genomes using RegulomeDB","volume":"22","author":"AP Boyle","year":"2012","journal-title":"Genome Res"},{"key":"pone.0242684.ref032","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Tissue-based map of the human proteome","volume":"347","author":"M Uhl\u00e9n","year":"2015","journal-title":"Science"},{"key":"pone.0242684.ref033","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ydbio.2008.07.006","article-title":"Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion","volume":"322","author":"T Nekrasova","year":"2008","journal-title":"Dev Biol"},{"key":"pone.0242684.ref034","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"GTEx Consortium\u2013Lead Analysts","year":"2017","journal-title":"Nature"},{"key":"pone.0242684.ref035","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"K Watanabe","year":"2017","journal-title":"Nat Commun"},{"key":"pone.0242684.ref036","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nmeth.1906","article-title":"ChromHMM: automating chromatin-state discovery and characterization","volume":"9","author":"J Ernst","year":"2012","journal-title":"Nat Methods"},{"key":"pone.0242684.ref037","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.celrep.2016.10.061","article-title":"A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome","volume":"17","author":"AD Schmitt","year":"2016","journal-title":"Cell Rep"},{"key":"pone.0242684.ref038","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"Integrative analysis of 111 reference human epigenomes","volume":"518","author":"Roadmap Epigenomics Consortium","year":"2015","journal-title":"Nature"},{"key":"pone.0242684.ref039","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s41588-018-0152-6","article-title":"Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence","volume":"50","author":"JE Savage","year":"2018","journal-title":"Nat Genet"},{"key":"pone.0242684.ref040","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/s41588-018-0151-7","article-title":"Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways","volume":"50","author":"M Nagel","year":"2018","journal-title":"Nat Genet"},{"key":"pone.0242684.ref041","doi-asserted-by":"crossref","first-page":"e271","DOI":"10.1212\/NXG.0000000000000271","article-title":"Plasticity-related gene 3 (LPPR1) and age at diagnosis of Parkinson disease","volume":"4","author":"ZD Wallen","year":"2018","journal-title":"Neurol Genet"},{"key":"pone.0242684.ref042","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/mp.2011.157","article-title":"Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder","volume":"18","author":"DT Chen","year":"2013","journal-title":"Mol Psychiatry"},{"key":"pone.0242684.ref043","doi-asserted-by":"crossref","first-page":"e3656","DOI":"10.1371\/journal.pone.0003656","article-title":"Rest-Mediated Regulation of Extracellular Matrix Is Crucial for Neural Development","volume":"3","author":"YM Sun","year":"2008","journal-title":"PLoS One"},{"key":"pone.0242684.ref044","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s10048-008-0154-0","article-title":"Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation","volume":"10","author":"B Bartelt-Kirbach","year":"2009","journal-title":"Neurogenetics"},{"key":"pone.0242684.ref045","doi-asserted-by":"crossref","first-page":"4072","DOI":"10.1093\/hmg\/ddq307","article-title":"A genome-wide scan for common alleles affecting risk for autism","volume":"19","author":"R Anney","year":"2010","journal-title":"Hum Mol Genet"},{"key":"pone.0242684.ref046","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1093\/hmg\/ddn388","article-title":"Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis","volume":"18","author":"SE Baranzini","year":"2009","journal-title":"Hum Mol Genet"},{"key":"pone.0242684.ref047","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1126\/science.1247761","article-title":"The Stum Gene Is Essential for Mechanical Sensing in Proprioceptive Neurons","volume":"343","author":"BS Desai","year":"2014","journal-title":"Science"},{"key":"pone.0242684.ref048","doi-asserted-by":"crossref","first-page":"4088","DOI":"10.1002\/hbm.23650","article-title":"Genome-wide mediation analysis of psychiatric and cognitive traits through imaging phenotypes","volume":"38","author":"X Bi","year":"2017","journal-title":"Hum Brain Mapp"},{"key":"pone.0242684.ref049","doi-asserted-by":"crossref","first-page":"1487.e21","DOI":"10.1016\/j.neurobiolaging.2011.10.011","article-title":"Genome-wide study links MTMR7 gene to variant Creutzfeldt-Jakob risk","volume":"33","author":"P Sanchez-Juan","year":"2012","journal-title":"Neurobiol Aging"},{"key":"pone.0242684.ref050","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/jhg.2015.153","article-title":"Individual risk alleles of susceptibility to schizophrenia are associated with poor clinical and social outcomes","volume":"61","author":"S Sakamoto","year":"2016","journal-title":"J Hum Genet"},{"key":"pone.0242684.ref051","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/nature15540","article-title":"Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism","volume":"528","author":"DA Oldridge","year":"2015","journal-title":"Nature"},{"issue":"2","key":"pone.0242684.ref052","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1155\/2013\/519419","article-title":"Identification of a novel quantitative trait nucleotype related to iron status in a calcium channel gene","volume":"34","author":"C Baeza-Richer","year":"2013","journal-title":"Disease Markers"},{"key":"pone.0242684.ref053","doi-asserted-by":"crossref","first-page":"5126","DOI":"10.1093\/hmg\/ddv231","article-title":"Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region","volume":"24","author":"Z Ning","year":"2015","journal-title":"Hum Mol Genet"},{"key":"pone.0242684.ref054","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1159\/000433599","article-title":"Characterization of a Novel Mutation in SLC1A1 Associated with Schizopshrenia","volume":"1","author":"P Afshari","year":"2015","journal-title":"Mol Neuropsychiatry"},{"key":"pone.0242684.ref055","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1001\/archpsyc.63.7.769","article-title":"Glutamate Transporter Gene SLC1A1 Associated With Obsessive-compulsive Disorder","volume":"63","author":"PD Arnold","year":"2006","journal-title":"Arch Gen Psychiatry"},{"key":"pone.0242684.ref056","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1002\/dvdy.22293","article-title":"Expression analysis of an evolutionary conserved metallophosphodiesterase gene, Mpped1, in the normal and \u03b2-catenin-deficient malformed dorsal telencephalon","volume":"239","author":"C-M Chen","year":"2010","journal-title":"Dev Dyn"},{"issue":"2","key":"pone.0242684.ref057","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.ajpath.2015.10.011","article-title":"Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2","volume":"186","author":"J Shen","year":"2016","journal-title":"Am J Pathol"},{"key":"pone.0242684.ref058","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.ajhg.2017.02.007","article-title":"Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome","volume":"100","author":"A Ta-Shma","year":"2017","journal-title":"Am J Hum Genet"},{"key":"pone.0242684.ref059","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/1471-2105-14-128","article-title":"Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool","volume":"14","author":"EY Chen","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"pone.0242684.ref060","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/mp.2013.138","article-title":"Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia","volume":"19","author":"DM Ruderfer","year":"2014","journal-title":"Mol Psychiatry"},{"key":"pone.0242684.ref061","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jalz.2015.05.020","article-title":"Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer\u2019s disease","volume":"12","author":"BW Kunkle","year":"2016","journal-title":"Alzheimer\u2019s Dement"},{"key":"pone.0242684.ref062","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0014-5793(98)01276-9","article-title":"The major myosin phosphatase in skeletal muscle is a complex between the beta-isoform of protein phosphatase 1 and the MYPT2 gene product","volume":"438","author":"G Moorhead","year":"1998","journal-title":"FEBS Lett"},{"key":"pone.0242684.ref063","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.cellsig.2005.11.001","article-title":"Characterization and function of MYPT2, a target subunit of myosin phosphatase in heart","volume":"18","author":"R Okamoto","year":"2006","journal-title":"Cell Signal"},{"key":"pone.0242684.ref064","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s12041-013-0210-x","article-title":"Validation of PPP1R12B as a candidate gene for childhood asthma in Russians","volume":"92","author":"MB Freidin","year":"2013","journal-title":"J Genet"},{"key":"pone.0242684.ref065","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12881-015-0190-1","article-title":"Genes involved in muscle contractility and nutrient signaling pathways within celiac disease risk loci show differential mRNA expression","volume":"16","author":"C Mont\u00e9n","year":"2015","journal-title":"BMC Med Genet"},{"key":"pone.0242684.ref066","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.placenta.2016.09.013","article-title":"Placental expression of DNA methyltransferase 1 (DNMT1): Gender-specific relations with human placental growth","volume":"48","author":"A Mukhopadhyay","year":"2016","journal-title":"Placenta"},{"key":"pone.0242684.ref067","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.devcel.2015.12.027","article-title":"Maternal DNA Methylation Regulates Early Trophoblast Development","volume":"36","author":"MR Branco","year":"2016","journal-title":"Dev Cell"},{"issue":"2","key":"pone.0242684.ref068","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S0169-328X(01)00014-6","article-title":"Splice isoforms of ubiquitous 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase in human brain.","volume":"87","author":"R Kessler","year":"2001","journal-title":"Brain Res Mol Brain Res."},{"key":"pone.0242684.ref069","doi-asserted-by":"crossref","first-page":"891","DOI":"10.7150\/ijms.19854","article-title":"Expression of epicardial adipose tissue thermogenic genes in patients with reduced and preserved ejection fraction heart failure","volume":"14","author":"LM 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Biol"},{"key":"pone.0242684.ref073","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/dmcn.12922","article-title":"Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations","volume":"58","author":"V Ricotti","year":"2016","journal-title":"Dev Med Child Neurol"},{"key":"pone.0242684.ref074","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0378-1119(97)00149-2","article-title":"The 239AB gene on chromosome 22: a novel member of an ancient gene family","volume":"194","author":"F Schwartz","year":"1997","journal-title":"Gene"},{"key":"pone.0242684.ref075","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13059-014-0560-6","article-title":"Gateways to the FANTOM5 promoter level mammalian expression atlas","volume":"16","author":"M Lizio","year":"2015","journal-title":"Genome Biol"},{"key":"pone.0242684.ref076","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1098\/rstl.1825.0026","article-title":"On the Nature of the Function Expressive of the Law of Human Mortality, and on a New Mode of Determining the Value of Life Contingencies","volume":"115","author":"B Gompertz","year":"1825","journal-title":"Phil Trans Royal Soc"},{"key":"pone.0242684.ref077","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0140-6736(07)60112-3","article-title":"Strategies to avoid the loss of developmental potential in more than 200 million children in the developing world","volume":"369","author":"PL Engle","year":"2007","journal-title":"Lancet"},{"key":"pone.0242684.ref078","volume-title":"Mixed-Effects Models in S and S-PLUS","author":"Springer","year":"2000"},{"key":"pone.0242684.ref079","unstructured":"Pinheiro JC, Bates D, DebRoy S, Sarkar D, R Core Team. nlme: Linear and Nonlinear Mixed Effects Models. 2019. R package version 3.1\u2013149."},{"key":"pone.0242684.ref080","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/BF02289159","article-title":"Multivariate information transmission","volume":"19","author":"WJ McGill","year":"1954","journal-title":"Psychometrika"},{"key":"pone.0242684.ref081","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1147\/rd.41.0066","article-title":"Information Theoretical Analysis of Multivariate Correlation","volume":"4","author":"S Watanabe","year":"1960","journal-title":"IBM J Res Dev"},{"key":"pone.0242684.ref082","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1093\/genetics\/138.3.963","article-title":"Empirical Threshold Values for Quantitative Trait Mapping","volume":"138","author":"GA Churchill","year":"1994","journal-title":"Genetics"},{"key":"pone.0242684.ref083","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"ENCODE Project Consortium","year":"2012","journal-title":"Nature"},{"key":"pone.0242684.ref084","doi-asserted-by":"crossref","first-page":"e1000778","DOI":"10.1371\/journal.pgen.1000778","article-title":"DNA Specificity Determinants Associate with Distinct Transcription Factor Functions","volume":"5","author":"PC Hollenhorst","year":"2009","journal-title":"PLoS Genet"},{"key":"pone.0242684.ref085","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1101\/gr.100552.109","article-title":"Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities","volume":"20","author":"A Jolma","year":"2010","journal-title":"Genome Res"},{"key":"pone.0242684.ref086","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.devcel.2010.10.006","article-title":"Differentiation-Specific Histone Modifications Reveal Dynasmic Chromatin Interactions and Partners for the Intestinal Transcription Factor 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One"},{"key":"pone.0242684.ref090","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.cell.2011.01.004","article-title":"Densely Interconnected Transcriptional Circuits Control Cell States in Human Hematopoiesis","volume":"144","author":"N Novershtern","year":"2011","journal-title":"Cell"},{"key":"pone.0242684.ref091","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/emboj.2010.342","article-title":"Differential genomic targeting of the transcription factor TAL1 in alternate haematopoietic lineages","volume":"30","author":"CG Palii","year":"2011","journal-title":"EMBO J"},{"key":"pone.0242684.ref092","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1182\/blood-2010-09-306563","article-title":"GABP controls a critical transcription regulatory module that is essential for maintenance and differentiation of hematopoietic stem\/progenitor cells","volume":"117","author":"S Yu","year":"2011","journal-title":"Blood"},{"key":"pone.0242684.ref093","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1038\/ng.2007.16","article-title":"A survey of genetic human cortical gene expression","volume":"39","author":"AJ Myers","year":"2007","journal-title":"Nat Genet"},{"key":"pone.0242684.ref094","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/ng2142","article-title":"Population genomics of human gene expression","volume":"39","author":"BE Stranger","year":"2007","journal-title":"Nat Genet"},{"key":"pone.0242684.ref095","doi-asserted-by":"crossref","first-page":"e107","DOI":"10.1371\/journal.pbio.0060107","article-title":"Mapping the Genetic Architecture of Gene Expression in Human Liver","volume":"6","author":"EE Schadt","year":"2008","journal-title":"PLoS Biol"},{"key":"pone.0242684.ref096","doi-asserted-by":"crossref","first-page":"e1000214","DOI":"10.1371\/journal.pgen.1000214","article-title":"High-Resolution Mapping of Expression-QTLs Yields Insight into Human Gene Regulation","volume":"4","author":"JB Veyrieras","year":"2008","journal-title":"PLoS Genet"},{"key":"pone.0242684.ref097","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1126\/science.1174148","article-title":"Common Regulatory Variation Impacts Gene Expression in a Cell Type-Dependent Manner","volume":"325","author":"AS Dimas","year":"2009","journal-title":"Science"},{"key":"pone.0242684.ref098","doi-asserted-by":"crossref","first-page":"e1000952","DOI":"10.1371\/journal.pgen.1000952","article-title":"Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain","volume":"6","author":"JR Gibbs","year":"2010","journal-title":"PLoS Genet"},{"key":"pone.0242684.ref099","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/nature08872","article-title":"Understanding mechanisms underlying human gene expression variation with RNA sequencing","volume":"464","author":"JK Pickrell","year":"2010","journal-title":"Nature"},{"key":"pone.0242684.ref100","doi-asserted-by":"crossref","first-page":"e10693","DOI":"10.1371\/journal.pone.0010693","article-title":"Genetics and Beyond\u2013The Transcriptome of Human Monocytes and Disease Susceptibility","volume":"5","author":"T Zeller","year":"2010","journal-title":"PLoS One"},{"key":"pone.0242684.ref101","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature10808","article-title":"DNase\u2009I sensitivity QTLs are a major determinant of human expression variation","volume":"482","author":"JF Degner","year":"2012","journal-title":"Nature"},{"key":"pone.0242684.ref102","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.cell.2011.11.013","article-title":"Comprehensive Genome-wide Protein-DNA Interactions Detected at Single-Nucleotide Resolution","volume":"147","author":"HS Rhee","year":"2011","journal-title":"Cell"},{"key":"pone.0242684.ref103","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1101\/gr.216747.116","article-title":"Quantifying the regulatory effect size of cis-acting genetic variation using allelic fold change","volume":"27","author":"P Mohammadi","year":"2017","journal-title":"Genome Res"},{"key":"pone.0242684.ref104","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nprot.2012.004","article-title":"Topological analysis and interactive visualization of biological networks and protein structures","volume":"7","author":"NT Doncheva","year":"2012","journal-title":"Nat Protoc"},{"key":"pone.0242684.ref105","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/bioinformatics\/btm554","article-title":"Computing topological parameters of biological networks","volume":"24","author":"Y 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