دورية أكاديمية
Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population.
| العنوان: | Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population. |
|---|---|
| المؤلفون: | Shimelis H; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Oetjens MT; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Walsh LK; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Wain KE; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Znidarsic M; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Myers SM; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Finucane BM; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Ledbetter DH; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors)., Martin CL; Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (all authors). |
| المصدر: | The American journal of psychiatry [Am J Psychiatry] 2023 Jan 01; Vol. 180 (1), pp. 65-72. Date of Electronic Publication: 2022 Dec 07. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Psychiatric Association Country of Publication: United States NLM ID: 0370512 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1535-7228 (Electronic) Linking ISSN: 0002953X NLM ISO Abbreviation: Am J Psychiatry Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Arlington, VA : American Psychiatric Association |
| مواضيع طبية MeSH: | Schizophrenia*/epidemiology , Schizophrenia*/genetics, Humans ; Penetrance ; Prevalence ; Genetic Testing ; Delivery of Health Care ; DNA Copy Number Variations/genetics |
| مستخلص: | Objective: Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population. Methods: The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger's MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs. Results: Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits. Conclusions: Collectively, rare single-gene variants and CNVs were found in >1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support. |
| التعليقات: | Comment in: Am J Psychiatry. 2023 Jan 1;180(1):11-13. (PMID: 36587271) |
| References: | Am J Hum Genet. 2019 Aug 1;105(2):267-282. (PMID: 31327507) Genet Med. 2020 Feb;22(2):245-257. (PMID: 31690835) Mol Psychiatry. 2016 Jul;21(7):885-93. (PMID: 27217147) Hum Mutat. 2018 Nov;39(11):1517-1524. (PMID: 30192042) Genome Med. 2017 May 30;9(1):43. (PMID: 28554332) Genet Med. 2022 Mar;24(3):703-711. (PMID: 34906480) J Med Genet. 2019 Mar;56(3):131-138. (PMID: 30343275) Nature. 2018 Oct;562(7726):203-209. (PMID: 30305743) Lancet. 2015 Apr 4;385(9975):1305-14. (PMID: 25529582) Nature. 2014 Nov 13;515(7526):216-21. (PMID: 25363768) Genet Med. 2016 Sep;18(9):906-13. (PMID: 26866580) PLoS Genet. 2017 Nov 29;13(11):e1007104. (PMID: 29186148) JAMA Netw Open. 2020 May 1;3(5):e203382. (PMID: 32383744) Nat Genet. 2017 Aug;49(8):1167-1173. (PMID: 28650482) Nat Genet. 2019 Jan;51(1):106-116. (PMID: 30559488) Cell. 2014 Jul 17;158(2):263-276. (PMID: 24998929) J Pers Med. 2021 May 01;11(5):. (PMID: 34062946) Nature. 2020 May;581(7809):434-443. (PMID: 32461654) JAMA Psychiatry. 2020 Dec 1;77(12):1276-1285. (PMID: 32697297) Genet Med. 2019 Jul;21(7):1611-1620. (PMID: 30504930) Am J Hum Genet. 2018 Jun 7;102(6):1204-1211. (PMID: 29861106) Autism Res. 2019 Dec;12(12):1728-1736. (PMID: 31705629) Front Genet. 2019 Apr 03;10:258. (PMID: 31001316) Am J Hum Genet. 2019 Feb 7;104(2):275-286. (PMID: 30665703) Nature. 2014 Jan 16;505(7483):361-6. (PMID: 24352232) JAMA Psychiatry. 2016 Mar;73(3):275-83. (PMID: 26817790) Cell. 2019 Aug 8;178(4):850-866.e26. (PMID: 31398340) JAMA. 2015 May 26;313(20):2044-54. (PMID: 26010633) Science. 2016 Dec 23;354(6319):. (PMID: 28008009) Nature. 2017 Feb 23;542(7642):433-438. (PMID: 28135719) Genet Med. 2015 May;17(5):405-24. (PMID: 25741868) Mol Autism. 2013 Oct 03;4(1):36. (PMID: 24090431) MMWR Morb Mortal Wkly Rep. 2018 Aug 17;67(32):882-887. (PMID: 30114005) Curr Opin Genet Dev. 2021 Jun;68:1-8. (PMID: 33434711) Lancet Neurol. 2013 Apr;12(4):406-14. (PMID: 23518333) Genet Med. 2016 Apr;18(4):302-4. (PMID: 26158229) Nat Neurosci. 2020 Feb;23(2):185-193. (PMID: 31932770) Pediatrics. 2019 Oct;144(4):. (PMID: 31558576) Genome Med. 2017 Dec 20;9(1):114. (PMID: 29262854) Nat Neurosci. 2016 Sep;19(9):1194-6. (PMID: 27479843) Am J Hum Genet. 2018 May 3;102(5):874-889. (PMID: 29727688) JAMA Psychiatry. 2015 Feb;72(2):119-26. (PMID: 25493922) |
| معلومات مُعتمدة: | R01 MH074090 United States MH NIMH NIH HHS; U01 MH119705 United States MH NIMH NIH HHS |
| فهرسة مساهمة: | Keywords: Bipolar and Related Disorders; Genetics/Genomics; Neurodevelopmental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders |
| تواريخ الأحداث: | Date Created: 20221207 Date Completed: 20230103 Latest Revision: 20240102 |
| رمز التحديث: | 20240102 |
| مُعرف محوري في PubMed: | PMC10017070 |
| DOI: | 10.1176/appi.ajp.22010062 |
| PMID: | 36475376 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1535-7228 |
|---|---|
| DOI: | 10.1176/appi.ajp.22010062 |