Evidence map›Paper›PMID 42094142›Full record

ArticlemedRxiv : the preprint server for health sciences2026

Combinatorial effects of gene dosage, polygenic background and environment on complex traits.

Molly F Sacks, Marieke Klein, Tim B Bigdeli, Mart Kals, Matthew T Oetjens, Florian Bénitière, Jacquelyn Johnson, Adam Maihofer, Margit Nõukas, Michael Francis and 44 more

Abstract readPreprint
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

54 authors.

Molly F SacksBioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.ORCID 0009-0007-6990-607X
Marieke KleinDepartment of Medical Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Tim B BigdeliVA New York Harbor Healthcare System, New York, NY, USA.
Mart KalsEstonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Matthew T OetjensDepartment of Developmental Medicine, Geisinger College of Health Sciences, Danville, PA, USA.
Florian BénitièreCHU Sainte-Justine Research Centre, Université de Montréal, Canada.
Jacquelyn JohnsonDepartment of Psychiatry and Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Adam MaihoferDepartment of Psychiatry and Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Margit NõukasEstonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Michael FrancisCenter for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA, USA.
Bryan GormanCenter for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA, USA.
Iskander SaidCenter for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA, USA.
Giulio GenoveseStanley Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Georgios VoloudakisCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Kyriacos MarkianosCenter for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA, USA.
Murray SteinDepartment of Psychiatry and Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Joel GelernterDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
David H LedbetterFlorida Institute for Pediatric Rare Diseases, Tallahassee, FL, USA.
Caroline M NievergeltDepartment of Psychiatry and Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Christa Lese MartinDepartment of Developmental Medicine, Geisinger College of Health Sciences, Danville, PA, USA.
Vincent-Raphaël BourqueCHU Sainte-Justine Research Centre, Université de Montréal, Canada.
Omar ShantaBioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
Jeffrey R MacDonaldThe Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Bhooma ThiruvahindrapuramThe Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Mamad AhangariDepartment of Psychiatry and Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Anjali SrinivasanBioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
James GuevaraDepartment of Psychiatry and Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Jessica H HallDivision of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Josephine E HaddonDivision of Psychological Medicine and Clinical Neurosciences, Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
Claudia VingerhoetsSchool for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
David LindenSchool for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
Mieke M van HaelstAmsterdam UMC, University of Amsterdam, Department of Human Genetics, Meibergdreef, Amsterdam, The Netherlands.
Marianne B M van den BreeCentre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK.
Carrie E BeardenDepartment of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Raquel E GurDepartment of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
T Blaine Crowley22q and You Center and Division of Genetic and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Daniel E McGinn22q and You Center and Division of Genetic and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Beverly S Emanuel22q and You Center and Division of Genetic and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Elaine H Zackai22q and You Center and Division of Genetic and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Ann SwillenDepartment of Human Genetics, KU Leuven, Leuven, Belgium.
Thérèse van AmelsvoortMental Health & Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands.
Jacob VorstmanDepartment of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada.
Anne S BassettDepartment of Psychiatry, University of Toronto, Toronto, ON, Canada.
Donna M McDonald-McGinn22q and You Center and Division of Genetic and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Panos RoussosCenter for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mihaela AslanVeterans Affairs Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
Philip D HarveyDepartment of Psychiatry, University of Miami Miller School of Medicine, Miami, FL, USA.
Million Veteran Program, Estonian Biobank Research Team
Genes to Mental Health Network
Sébastien JacquemontCentre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada.
Saiju PyarajanCenter for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA, USA.
Kelli LehtoEstonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Peter M VisscherNuffield Department of Population Health, University of Oxford, Oxford, UK.
Jonathan SebatDepartment of Psychiatry and Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.

Funding

ProNET: Psychosis-Risk Outcomes NetworkU01MH124639 · NIMH · YALE UNIVERSITY · PI CARRIE E BEARDEN, JOHN M KANE · 2020 to 2026
$81.2M
Understanding the molecular mechanisms that contribute to neuropsychiatric symptoms in Alzheimer DiseaseR01AG067025 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI FINKBEINER, STEVEN M, HAROUTUNIAN, VAHRAM · 2019 to 2023
$11.8M
Leveraging rare genetic etiologies to advance knowledge and treatment of neurpsychiatric disordersU01MH119705 · NIMH · GEISINGER CLINIC · PI LEDBETTER, DAVID H., MARTIN, CHRISTA LESE · 2019 to 2023
$9.2M
Psychiatric Genomics Consortium for PTSDR01MH106595 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KARESTAN C KOENEN, Caroline M Nievergelt · 2016 to 2026
$8.4M
The BrainCellQTL consortium: QTL mapping in the human brain at the single cell levelU24AG087563 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Panagiotis Roussos · 2024 to 2026
$7.2M
Neurodevelopment and Psychosis in the 22q11.2 Deletion SyndromeR01MH085953 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI BEARDEN, CARRIE E · 2010 to 2020
$6.2M
The 3D genome in transcriptional regulation across the postnatal life span, with implications for schizophrenia and bipolar disorderU01MH116442 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI AKBARIAN, SCHAHRAM, DRACHEVA, STELLA · 2018 to 2022
$5.9M
Large-Scale Evaluation of the Effect of Rare Genetic Variants on Psychiatric Symptoms and Cognitive AbilityU01MH119690 · NIMH · BOSTON CHILDREN'S HOSPITAL · PI ALMASY, LAURA A., GLAHN, DAVID C · 2019 to 2023
$5.9M
Multiethnic genomic epigenomic and transcriptomic fine-mapping and functional validation analysis of schizophrenia and bipolar disorder risk lociR01MH125246 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI ROUSSOS, PANAGIOTIS · 2021 to 2025
$5.0M
Elucidating the Interplay of Genes and Environment in Autism Using Genomic and Exposure Data from Large PopulationsOT2OD040415 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SEBAT, JONATHAN · 2025 to 2025
$3.9M
1/9: Dissecting the effects of genomic variants on nenriched for neuropsychiatric disorderseurobehavioral dimensions in CNVs U01MH119738 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI GUR, RAQUEL E · 2019 to 2023
$3.2M
1/2: Neurodevelopmental Trajectories in 22q11.2 Deletion Syndrome in Adolescence and Young AdulthoodR01MH134969 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI Raquel E Gur · 2024 to 2026
$2.5M
BLRD VA I01 BX004189BLRD VA I01 BX005920CSRD VA I01 CX001849NIA NIH HHS R01 AG067025NIA NIH HHS U24 AG087563NIH HHS OT2 OD040415NIMH NIH HHS R01 MH085953NIMH NIH HHS R01 MH106595NIMH NIH HHS R01 MH125246NIMH NIH HHS R01 MH129858NIMH NIH HHS R01 MH134965NIMH NIH HHS R01 MH134969NIMH NIH HHS R21 MH116473NIMH NIH HHS U01 MH101724NIMH NIH HHS U01 MH116442NIMH NIH HHS U01 MH119690NIMH NIH HHS U01 MH119705NIMH NIH HHS U01 MH119736NIMH NIH HHS U01 MH119737NIMH NIH HHS U01 MH119738NIMH NIH HHS U01 MH119739NIMH NIH HHS U01 MH119746NIMH NIH HHS U01 MH119758NIMH NIH HHS U01 MH119759NIMH NIH HHS U01 MH124639Wellcome Trust
6 · The paper itself

Abstract

Complex traits arise from the combined effects of rare and common genetic variation, development and environment, but resolving their joint contributions has been limited by statistical power. Here, we meta-analyze effects of recurrent copy number variants (CNVs), polygenic scores, sex, age and medications on height and body mass index in 1,447,001 individuals across 6 biobanks and clinical cohorts. CNVs show largely mirror dose-dependent effects of deletions and duplications on both traits, but a subset of loci exhibit asymmetric dose-responses on adult height, consistent with buffering of one allele but not the other. Polygenic background and medications combine with CNVs in ways broadly consistent with additivity. However, detailed analyses of loci at 16p11.2 and 22q11.2 reveal context-dependent effects that vary across development, physiology and sex. At 22q11.2, the net effect of a CNV reflects opposing and reinforcing contributions of multiple genes, providing a potential mechanism for buffering of dosage effects. These results indicate that genetic effects follow additive patterns in aggregate, while context-dependent deviations are widespread for specific loci.

Identifiers

PMID42094142
PMCPMC13142611

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.