Evidence map›Paper›PMID 35716666›Full record

ArticleAmerican journal of human genetics2022

Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits.

Roshni A Patel, Shaila A Musharoff, Jeffrey P Spence, Harold Pimentel, Catherine Tcheandjieu, Hakhamanesh Mostafavi, Nasa Sinnott-Armstrong, Shoa L Clarke, Courtney J Smith, V.A. Million Veteran Program and 15 more

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In one paragraph

Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
55citing papers in PubMed, 2 pooled it
14.2field-weighted citation impact, top 1% of its field
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

55 citing papers in PubMed, 2 syntheses or guidelines pooled it, 78 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Testing for Genetic Interactions in Complex Disease With Distance Correlation.Biometrical journal. Biometrische Zeitschrift · 2026
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  8. Observational epidemiological studies can mitigate genetic confounding with a genetic relatedness matrix.Proceedings of the National Academy of Sciences of the United States of America · 2026
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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

25 authors at 10 institutions in 1 country.

Roshni A PatelGenetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: rpatel7@stanford.edu.
Shaila A MusharoffGenetics, Stanford University School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA.
Jeffrey P SpenceGenetics, Stanford University School of Medicine, Stanford, CA, USA.
Harold PimentelComputational Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Catherine TcheandjieuVA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University School of Medicine, Stanford, CA, USA.
Hakhamanesh MostafaviGenetics, Stanford University School of Medicine, Stanford, CA, USA.
Nasa Sinnott-ArmstrongGenetics, Stanford University School of Medicine, Stanford, CA, USA; VA Palo Alto Health Care System, Palo Alto, CA, USA.
Shoa L ClarkeVA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University School of Medicine, Stanford, CA, USA.
Courtney J SmithGenetics, Stanford University School of Medicine, Stanford, CA, USA.
V.A. Million Veteran Program
Peter P DurdaThe Robert Larner, M.D. College of Medicine at The University of Vermont, Burlington, VT, USA.
Kent D TaylorInstitute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Russell TracyThe Robert Larner, M.D. College of Medicine at The University of Vermont, Burlington, VT, USA.
Yongmei LiuDuke University School of Medicine, Durham, NC, USA.
W Craig JohnsonBiostatistics, University of Washington, Seattle, WA, USA.
Francois AguetBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Kristin G ArdlieBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Stacey GabrielBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Josh SmithGenome Sciences, University of Washington, Seattle, WA, USA.
Deborah A NickersonGenome Sciences, University of Washington, Seattle, WA, USA.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Jerome I RotterInstitute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Philip S TsaoVA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University School of Medicine, Stanford, CA, USA.
Themistocles L AssimesVA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University School of Medicine, Stanford, CA, USA.
Jonathan K PritchardGenetics, Stanford University School of Medicine, Stanford, CA, USA; Biology, Stanford University, Stanford, CA, USA. Electronic address: pritch@stanford.edu.
VA Palo Alto Health Care System · USStanford University · USBroad Institute · USUniversity of Washington · USUCLA Medical Center · USUniversity of Vermont · USDuke University · USStanford Medicine · USUniversity of California, Los Angeles · USUniversity of Virginia · US

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
Stanford Center for Clinical & Translational Education and Research (Spectrum)UL1TR003142 · NCATS · STANFORD UNIVERSITY · PI O'HARA, RUTH M · 2019 to 2023
$45.0M
INSTITUTIONAL TRAINING GRANT IN GENOME SCIENCET32HG000044 · NHGRI · STANFORD UNIVERSITY · PI MICHAEL P. SNYDER · 1995 to 2026
$32.2M
Studies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5M
CHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5M
Rare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9M
Integration of genetic association mapping and functional data to elucidate genetic mechanisms of diseaseR01HG008140 · NHGRI · STANFORD UNIVERSITY · PI JONATHAN K PRITCHARD · 2016 to 2026
$7.3M
Rare variants and NHLBI traits in deeply phenotyped cohortsU01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2017 to 2018
$5.6M
Decoding the regulatory architecture of the human genome across cell types, individuals and diseaseU01HG009431 · NHGRI · STANFORD UNIVERSITY · PI PRITCHARD, JONATHAN K · 2017 to 2021
$3.5M
New methods for constructing and evaluating polygenic scoresR01HG011432 · NHGRI · STANFORD UNIVERSITY · PI PRITCHARD, JONATHAN K · 2020 to 2023
$3.3M
Integrative multi-omics in whole genome studies of HLBS disordersR01HL142015 · NHLBI · STANFORD UNIVERSITY · PI MONTGOMERY, STEPHEN · 2018 to 2019
$882k
Genetics of Cardiometabolic Diseases in the VA PopulationI01BX003362 · VA · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · PI Kyong-Mi Chang, Philip S Tsao · 2017 to 2026
–
BLRD VA I01 BX003362NCATS NIH HHS UL1 TR003142NHGRI NIH HHS R01 HG008140NHGRI NIH HHS R01 HG011432NHGRI NIH HHS T32 HG000044NHGRI NIH HHS U01 HG009431NHGRI NIH HHS U54 HG003067NHLBI NIH HHS HHSN268201000021CNHLBI NIH HHS HHSN268201600038CNHLBI NIH HHS HHSN268201600041CNHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL142015NHLBI NIH HHS U01 HL120393NIEHS NIH HHS HHSN268201600032C
6 · The paper itself

Abstract

Despite the growing number of genome-wide association studies (GWASs), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWASs are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate, although this is not significant, most likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.

Indexed as

Genome-Wide Association StudyMultifactorial InheritanceCholesterol, LDLGene ExpressionHumansPolymorphism, Single NucleotideWhite PeopleCholesterol, LDLcomplex traitsgenetic correlationgenome-wide associationpopulation geneticsstatistical genetics

Identifiers

PMID35716666
PMCPMC9300878
OpenAlexW4283032622

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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 OpenQuestion graph.