Lora McClain1, Hader Mansour2, Ibtihal Ibrahim3, Lambertus Klei1, Warda Fathi3, Joel Wood1, Chowdari Kodavali1, Alina Maysterchuk1, Shawn Wood1, Farha El-Chennawi4, Nahed Ibrahim1, Ahmed Eissa5, Wafaa El-Bahaei3, Hanan El Sayed3, Amal Yassein3, Salwa Tobar3, Hala El-Boraie3, Eman El-Sheshtawy3, Hala Salah3, Ahmed Ali6, Serkan Erdin7, Bernie Devlin1, Michael Talkowski7, Vishwajit Nimgaonkar8. 1. Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Hospital, Pittsburgh, PA, USA. 2. Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Hospital, Pittsburgh, PA, USA; Department of Psychiatry, Mansoura University School of Medicine, Mansoura, Egypt. 3. Department of Psychiatry, Mansoura University School of Medicine, Mansoura, Egypt. 4. Department of Clinical Pathology, Mansoura University School of Medicine, Mansoura, Egypt. 5. Department of Psychiatry and Neuropsychiatry, Port Said University, Port Said, Egypt. 6. Department of Clinical Pathology, Mansoura University Student Hospital, Mansoura, Egypt. 7. Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA, USA. 8. Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Hospital, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: vishwajitnl@upmc.edu.
Abstract
BACKGROUND: Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. METHODS: We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. RESULTS: Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. CONCLUSIONS: We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.
BACKGROUND: Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. METHODS: We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. RESULTS: Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. CONCLUSIONS: We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.
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