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We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR &amp;lt; 0.05 while the other results were suggestive with 0.18 \u2264 FDR \u2264 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like <jats:italic>APOBEC3G, H6PD, SLC45A1, GRIN3B<\/jats:italic>, and <jats:italic>PDE4D<\/jats:italic> were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the <jats:italic>SLC45A1<\/jats:italic> gene, which was upregulated with increasing cognitive function. Linear models found only <jats:italic>H6PD<\/jats:italic> and <jats:italic>SLC45A1<\/jats:italic>, the other genes were captured by GCC. Significant functional pathways (FDR &amp;lt; 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR&amp;lt; 1.3e-4) were enriched in a transcriptional regulatory analysis in which <jats:italic>CTCF<\/jats:italic> and <jats:italic>REST<\/jats:italic> were activated and <jats:italic>SP3, SRF<\/jats:italic>, and <jats:italic>XBP1<\/jats:italic> were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.<\/jats:p>","DOI":"10.3389\/fgene.2021.675587","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:09:01Z","timestamp":1623665341000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins"],"prefix":"10.3389","volume":"12","author":[{"given":"Afsaneh","family":"Mohammadnejad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper Beltoft","family":"Lund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Mengel-From","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja Maria","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene","family":"Christiansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaare","family":"Christensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Hjelmborg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Baumbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihua","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.2174\/0929867033456918","article-title":"Role of cytokines in neurological disorders","volume":"10","author":"Aarli","year":"2005","journal-title":"Curr. 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