{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T20:03:38Z","timestamp":1776024218412,"version":"3.50.1"},"reference-count":84,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T00:00:00Z","timestamp":1682640000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["P41 GM103504"],"award-info":[{"award-number":["P41 GM103504"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HG009979"],"award-info":[{"award-number":["R01 HG009979"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institute for Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>An open challenge in human genetics is to better understand the systems-level impact of genotype variation on developmental cognition. To characterize the genetic underpinnings of peri-adolescent cognition, we performed genotype\u2013phenotype and systems analysis for binarized accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (~2,200 individuals of European continental ancestry aged 8\u201321\u00a0years). We report a region of genome-wide significance within the 3\u2032 end of the Fibulin-1 gene (P\u00a0=\u20094.6\u2009\u00d7\u200910\u22128), associated with accuracy in nonverbal reasoning, a heritable form of complex reasoning ability. Diffusion tensor imaging data from a subset of these participants identified a significant association of white matter fractional anisotropy with FBLN1 genotypes (P\u00a0&amp;lt;\u20090.025); poor performers show an increase in the C and A allele for rs77601382 and rs5765534, respectively, which is associated with increased fractional anisotropy. Integration of published human brain-specific \u2019omic maps, including single-cell transcriptomes of the developing human brain, shows that FBLN1 demonstrates greatest expression in the fetal brain, as a marker of intermediate progenitor cells, demonstrates negligible expression in the adolescent and adult human brain, and demonstrates increased expression in the brain in schizophrenia. Collectively these findings warrant further study of this gene and genetic locus in cognition, neurodevelopment, and disease. Separately, genotype-pathway analysis identified an enrichment of variants associated with working memory accuracy in pathways related to development and to autonomic nervous system dysfunction. Top-ranking pathway genes include those genetically associated with diseases with working memory deficits, such as schizophrenia and Parkinson\u2019s disease. This work advances the \u201cmolecules-to-behavior\u201d view of cognition and provides a framework for using systems-level organization of data for other biomedical domains.<\/jats:p>","DOI":"10.1093\/cercor\/bhad142","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T05:15:10Z","timestamp":1682658910000},"page":"8581-8593","source":"Crossref","is-referenced-by-count":1,"title":["Multi-scale systems genomics analysis predicts pathways, cell types, and drug targets involved in normative variation in peri-adolescent human cognition"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-581X","authenticated-orcid":false,"given":"Shraddha","family":"Pai","sequence":"first","affiliation":[{"name":"The Donnelly Centre, University of Toronto , Toronto , Canada"},{"name":"Adaptive Oncology, Ontario Institute for Cancer Research , Toronto , Canada"},{"name":"Department of Medical Biophysics, University of Toronto , Toronto , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6428-5880","authenticated-orcid":false,"given":"Shirley","family":"Hui","sequence":"additional","affiliation":[{"name":"The Donnelly Centre, University of Toronto , Toronto , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3101-6817","authenticated-orcid":false,"given":"Philipp","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Southern Denmark , Odense , Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soumil","family":"Narayan","sequence":"additional","affiliation":[{"name":"The Donnelly Centre, University of Toronto , Toronto , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3392-232X","authenticated-orcid":false,"given":"Owen","family":"Whitley","sequence":"additional","affiliation":[{"name":"The Donnelly Centre, University of Toronto , Toronto , Canada"},{"name":"Department of Molecular Genetics, University of Toronto , Toronto , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5761-9814","authenticated-orcid":false,"given":"Peipei","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Science, Van Andel Research Institute , Grand Rapids, MI , United States"},{"name":"Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University , Grand Rapids, MI , United 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L","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Neurosciences and Mental Health, The Hospital for Sick Children , Toronto , Canada"},{"name":"Department of Physiology, University of Toronto , Toronto , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0185-8861","authenticated-orcid":false,"given":"Gary D","family":"Bader","sequence":"additional","affiliation":[{"name":"The Donnelly Centre, University of Toronto , Toronto , Canada"},{"name":"Department of Molecular Genetics, University of Toronto , Toronto , Canada"},{"name":"Department of Computer Science, University of Toronto , Toronto , Canada"},{"name":"The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto , 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