ArticlePLoS genetics2021
Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios.
Article in PLoS genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 3 of them syntheses that pooled it.
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Who cites it
40 citing papers in PubMed, 3 syntheses or guidelines pooled it, 46 citations in OpenAlex.
- Investigating the shared genetic architecture between selective immunoglobulin A deficiency and autoimmune diseases.Human genetics · 2026Pooled it
- Genetic heterogeneity and homogeneity among orofacial cleft subtypes: genome-wide association studies in the cleft collective.Human molecular genetics · 2025Pooled it
- A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores.Molecular neurodegeneration · 2023Pooled it
- Trio-based GWAS reveals loci associated with different forms of isolated cleft lip.HGG advances · 2026Article
- A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping.medRxiv : the preprint server for health sciences · 2026Article
- Exploring the Shared Genetic Basis of Age at Menopause and Osteoarthritis.ACR open rheumatology · 2026Article
- Maternal agrochemical exposure during pregnancy and risk of orofacial clefts: a case-control study in eight low- and middle-income countries.Journal of exposure science & environmental epidemiology · 2026Article
- Genetic insights into the relationship between age at menarche and mental health-related phenotypes.European psychiatry : the journal of the Association of European Psychiatrists · 2026Article
- Trio-based GWAS reveals novel loci associated with different forms of isolated cleft lip.medRxiv : the preprint server for health sciences · 2026Article
- Cross-trait genomic and sequential analyses of multiple omics datasets identified shared genetic components for the gut-eye axis.Human genomics · 2026Article
- CircadianiScience · 2026Article
- Shared Genetic Basis and Causality Between Epilepsy and Psychiatric Disorders: Evidence From a Comprehensive Genetic Analysis.Brain and behavior · 2026Article
- Identifying pleiotropic genes for backfat thickness and semen traits in pigs using GWAS summary data.Journal of animal science · 2026Article
- Shared genetic architecture and potential comorbid mechanisms between rheumatoid arthritis and idiopathic pulmonary fibrosis.Clinical rheumatology · 2026Article
- Comprehensive Genome-Wide Analysis of Shared Genetic Factors in Gastrointestinal and Neurodegenerative Diseases.Brain and behavior · 2025Article
- The shared genetic architecture between schizophrenia and common peripheral organ imaging phenotypes.Schizophrenia (Heidelberg, Germany) · 2025Article
- Shared genetics of lung cancer and type 2 diabetes: a large-scale genome-wide cross-trait analysis.Translational lung cancer research · 2025Article
- Genomic Correlations, Shared Loci, and Drug Targets Between Polycystic Ovary Syndrome and Asthma: Insights From Genome-wide Association Analysis.The Journal of clinical endocrinology and metabolism · 2025Article
- Article
- Dissecting the genetic determinants and biological associations between body mass index and female reproductive disorders based on genome-wide association study.Reproductive biology and endocrinology : RB&E · 2025Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts- the most common craniofacial birth defects in humans- are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 has been recognized as significantly associated with both CL/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 × 10-8, PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10-6, we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of both CL/P and CP in the same direction. We found locus-specific effects may vary by racial/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Our in-silico validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.
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