Assortative mating and parental genetic relatedness drive the pathogenicity of variably expressive variants.

Autor: Smolen C; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA., Jensen M; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA., Dyer L; GeneDx, Gaithersburg, MD 20877, USA., Pizzo L; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., Tyryshkina A; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Neuroscience Graduate program, Pennsylvania State University, University Park, PA 16802., Banerjee D; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA., Rohan L; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., Huber E; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., El Khattabi L; Assistance Publique-Hôpitaux de Paris, Department of Medical Genetics, Armand Trousseau and Pitié-Salpêtrière Hospitals, Paris, France., Prontera P; Medical Genetics Unit, Hospital 'Santa Maria della Misericordia', Perugia, Italy., Caberg JH; Centre Hospitalier Universitaire de Liège. Domaine Universitaire du Sart Tilman, Liège, Belgium., Van Dijck A; Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium., Schwartz C; Greenwood Genetic Center, Greenwood, SC 29646, USA., Faivre L; Centre de Genetique et Cenre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d'Enfants, CHU Dijon, Dijon, France.; GAD INSERM UMR1231, FHU TRANSLAD, Université de Bourgogne Franche Comté, Dijon, France., Callier P; Centre de Genetique et Cenre de Référence Anomalies du développement et syndromes malformatifs, Hôpital d'Enfants, CHU Dijon, Dijon, France.; GAD INSERM UMR1231, FHU TRANSLAD, Université de Bourgogne Franche Comté, Dijon, France., Mosca-Boidron AL; Laboratoire de Genetique Chromosomique et Moleculaire, CHU Dijon, France., Lefebvre M; GAD INSERM UMR1231, FHU TRANSLAD, Université de Bourgogne Franche Comté, Dijon, France., Pope K; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Snell P; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Lockhart PJ; Department of Paediatrics, University of Melbourne, Melbourne, Australia.; Bruce Lefroy Center, Murdoch Children's Research Institute, Melbourne, Australia., Castiglia L; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy., Galesi O; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy., Avola E; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy., Mattina T; Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy., Fichera M; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy.; Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy., Mandarà GML; Medical Genetics, ASP Ragusa, Ragusa, Italy., Bruccheri MG; Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy., Pichon O; CHU Nantes, Department of Medical Genetics, Nantes, France., Le Caignec C; CHU Toulouse, Department of Medical Genetics, Toulouse, France.; ToNIC, Toulouse Neuro Imaging, Center, Inserm, UPS, Université de Toulouse, Toulouse, France., Stoeva R; Service de Cytogenetique, CHU de Le Mans, Le Mans, France., Cuinat S; CHU Nantes, Department of Medical Genetics, Nantes, France., Mercier S; CHU Nantes, Department of Medical Genetics, Nantes, France., Bénéteau C; CHU Nantes, Department of Medical Genetics, Nantes, France., Blesson S; Department of Genetics, Bretonneau University Hospital, Tours, France., Nordsletten A; Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA., Martin-Coignard D; Department of Genetics, Bretonneau University Hospital, Tours, France., Sistermans E; Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands., Kooy RF; Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium., Amor DJ; Bruce Lefroy Center, Murdoch Children's Research Institute, Melbourne, Australia., Romano C; Medical Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.; Medical Genetics, ASP Ragusa, Ragusa, Italy., Isidor B; CHU Nantes, Department of Medical Genetics, Nantes, France., Juusola J; GeneDx, Gaithersburg, MD 20877, USA., Girirajan S; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.; Bioinformatics and Genomics Graduate program, Pennsylvania State University, University Park, PA 16802, USA.; Neuroscience Graduate program, Pennsylvania State University, University Park, PA 16802.; Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 May 26. Date of Electronic Publication: 2023 May 26.
DOI: 10.1101/2023.05.18.23290169
Abstrakt: We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p<0.001), and two measures of sub-clinical autism features in parents affecting several autism severity measures in children, such as bi-parental mean Social Responsiveness Scale (SRS) scores affecting proband SRS scores (regression coefficient=0.11, p=0.003). We further describe patterns of phenotypic and genetic similarity between spouses, where spouses show both within- and cross-disorder correlations for seven neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R=0.25-0.72, p<0.001) and a cross-disorder correlation between schizophrenia and personality disorder (R=0.20-0.57, p<0.001). Further, these spouses with similar phenotypes were significantly correlated for rare variant burden (R=0.07-0.57, p<0.0001). We propose that assortative mating on these features may drive the increases in genetic risk over generations and the appearance of "genetic anticipation" associated with many variably expressive variants. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse correlations with burden and pathogenicity of rare variants and propose that parental relatedness drives disease risk by increasing genome-wide homozygosity in children (R=0.09-0.30, p<0.001). Our results highlight the utility of assessing parent phenotypes and genotypes in predicting features in children carrying variably expressive variants and counseling families carrying these variants.
Databáze: MEDLINE