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Whether this pattern reflects statistical artifacts or real biological differences \u2014 and, if the latter, what underlies it \u2014 remains unclear. In addition to psychiatric disorders, we find that other traits with functional enrichment in the central nervous system (CNS), whether binary or quantitative, also share similar genetic architectures, characterized by GWAS hits of limited statistical significance and generally higher allele frequencies. To robustly compare traits that differ in GWAS statistical power, we demonstrate how binarizing a quantitative trait reduces power. This loss of power can be replicated by a matched \u201ceffective sample size\u201d on the liability scale. After matching \u201ceffective sample sizes\u201d, we show that CNS-enriched traits have large mutational target sizes, with contributing variants and genes experiencing stronger selection than those for other traits. Our findings reveal heterogeneity among diseases and provide insights into traits that more effectively capture fitness-relevant processes. More broadly, our results suggest that the genetic architectures of complex traits are shaped by the tissues through which these traits are mediated.<\/jats:p>","DOI":"10.64898\/2026.03.22.713538","type":"posted-content","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T08:55:15Z","timestamp":1774428915000},"source":"Crossref","is-referenced-by-count":3,"title":["Genetic architectures of brain-related traits are shaped by strong selective constraints"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0639-7002","authenticated-orcid":false,"given":"Huisheng","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0037-4673","authenticated-orcid":false,"given":"Yuval B.","family":"Simons","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University, Stanford, CA"},{"name":"Section of Genetic Medicine, University of Chicago, Chicago, IL"},{"name":"Department of Human Genetics, University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3199-1447","authenticated-orcid":false,"given":"Jeffrey P.","family":"Spence","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University, Stanford, CA"},{"name":"Institute for Human Genetics, University of California, San Francisco, CA"},{"name":"Department of Epidemiology & Biostatistics, University of California, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5239-7930","authenticated-orcid":false,"given":"Guy","family":"Sella","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Columbia University, New York City, NY"},{"name":"Program for Mathematical Genomics, Columbia University, New York City, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8828-5236","authenticated-orcid":false,"given":"Jonathan K.","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA"},{"name":"Department of Genetics, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032701552396000_2026.03.22.713538v1.1","doi-asserted-by":"publisher","DOI":"10.2307\/2841583"},{"key":"2026032701552396000_2026.03.22.713538v1.2","unstructured":"Falconer DS , Mackay TFC . 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