{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T07:44:18Z","timestamp":1778744658132,"version":"3.51.4"},"reference-count":43,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T00:00:00Z","timestamp":1571097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Missing heritability is a common problem in psychiatry that impedes precision medicine approaches to autism and other heritable complex disorders. This proof-of-concept study uses a systematic review and meta-analysis of the association between variants of the serotonin transporter promoter (5-HTTLPR) and autism to explore the hypothesis that some missing heritability can be explained using an optimum curve. A systematic literature search was performed to identify transmission disequilibrium tests on the short\/long (S\/L) 5-HTTLPR polymorphism in relation to autism. We analysed five American, seven European, four Asian and two American\/European samples. We found no transmission preference in the joint samples and in Europe, preferential transmission of S in America and preferential transmission of L in Asia. Heritability will be underestimated or missed in genetic association studies if two alternative genetic variants are associated with the same disorder in different subsets of a sample. An optimum curve, relating a multifactorial biological variable that incorporates genes and environment to a score for a human trait, such as social competence, can explain this. We suggest that variants of functionally related genes will sometimes appear in fixed combinations at both sides of an optimum curve and propose that future association studies should account for such combinations.<\/jats:p>","DOI":"10.3390\/ijms20205104","type":"journal-article","created":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T03:32:54Z","timestamp":1571196774000},"page":"5104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tackling Missing Heritability by Use of an Optimum Curve: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4977-1960","authenticated-orcid":false,"given":"Anneke","family":"Wegener Sleeswijk","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University Medical Center Utrecht Brain Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0724-5962","authenticated-orcid":false,"given":"Reinout","family":"Heijungs","sequence":"additional","affiliation":[{"name":"Department of Econometrics and Operations Research, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands"},{"name":"Institute of Environmental Sciences, Department of Industrial Ecology, Leiden University, Einsteinweg 2, 2333 CC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Durston","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University Medical Center Utrecht Brain Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/1745-6215-15-230","article-title":"Fluoxetine for Autistic Behaviors (FAB trial): Study protocol for a randomized controlled trial in children and adolescents with autism","volume":"15","author":"Mouti","year":"2014","journal-title":"Trials"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). 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