Abstract
Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders.
Highlights
Inbreeding is a well-established risk factor for recessive Mendelian diseases because it results in the presence of autozygosity regions, which are long runs of homozygosity (ROHs) in which the two alleles are identical by descent
A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that large autozygosity regions due to recent inbreeding could play a role in the disease [2]
Our results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia
Summary
Inbreeding is a well-established risk factor for recessive Mendelian diseases because it results in the presence of autozygosity regions, which are long runs of homozygosity (ROHs) in which the two alleles are identical by descent. These regions, increase the odds of bearing rare, recessive, deleterious mutations in a homozygous state (reviewed in [1]). Previous studies failed to detect a significant enrichment of rare recessive deleterious homozygous variants in the schizophrenic population [3, 4]. Mating between relatives accounts for fewer than 1% of marriages in industrialized countries [5]; the appearance of rare homozygous risk variants should be an ultra-rare event that is difficult to identify in the general population
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
