Whole Exome Sequencing In Arab And Jewish Israeli Families Multiply Affected With Schizophrenia

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Background

Schizophrenia is a complex disorder that likely results from the impact of both common and rare susceptibility variants. The impact of common variants with small effect in schizophrenia has been widely investigated. After large scale sequencing studies in schizophrenia become feasible, multiple whole exome sequencing studies were performed, and found disruptive mutations distributed across many different genes. They also identified gene sets with enrichment of rare variants with large effect. Sequencing studies performed in large families have showed that candidate variants did not necessarily segregate within the families, and were different in each family. To search for inherited variants of large effect we performed whole exome sequencing in Arab and Jewish Israeli families multiply affected with schizophrenia. All the Jewish families were of non-Ashkenazi origin. The Arab families were drawn from an ethnically homogenous population with an unusually high level of consanguinity, and a low rate of intermarriage with other population groups in Israel.

Methods

Eight large families with multiple subjects affected with schizophrenia were selected, since in these families the genetic transmission appears to be most consistent with inheritance of highly-penetrant disease alleles. In total whole exome sequencing and data analysis of 32 family members were performed. Each family was analyzed separately, first according to the most appropriate single-gene mode of inheritance and second according to an oligogenic mode of inheritance looking for all variants shared between affected family members. Multiple variants found by applying the oligogenic mode of inheritance were prioritized by using the VarElect software. To assess enrichment of rare segregating variants in specific genes in the schizophrenia cases, we performed a gene-based collapsing dominant model analysis while correcting for population stratification. Permutation-based analyses were done to test for enrichment of previously detected de-novo variants and additional candidate gene sets.

Results

We were able to identify several interesting rare segregating functional variants. Single-gene inheritance candidates which are consistent with the most appropriate mode of inheritance in a given family were found in only 2 out of 8 analyzed families. These variants were found in DOCK8 and DRP2 genes. No gene reached genome-wide significance in the collapsing analysis. An enrichment of variants in candidate gene sets is currently under investigation.

Discussion

It seems that schizophrenia in most of these families arises from the combined effects of several different coding variants, even in ethnically homogenous consanguineous Arab Israeli families.

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