Oligogenic Mode Of Inheritance Research Articles

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

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.

Oligogenic inheritance in neuroblastoma

Neuroblastoma (NB), a childhood malignancy affecting neural crest deriving cell lineages, is characterized by great clinical variability and histological heterogeneity. As NB usually occurs as sporadic form, molecular studies were mainly carried out on tumor samples and derived cell lines, leading to the identification of several somatic alterations. Although familial NB is rare, linkage data obtained from different families have provided evidence of linkage to markers mapping to different chromosomal regions, indicating a remarkable genetic heterogeneity of NB. The first evidence of germline mutations in NB pedigrees has been recently reported in the paired-like homeobox 2B ( PHOX2B) gene, involved in the development of neural crest deriving cells. Nevertheless, as only a few NB families but not others have been shown to carry PHOX2B mutations, the role of this gene in NB predisposition has still to be clarified. On the basis of the current data, familial NB cannot be modeled as a Mendelian monogenic trait. Instead, an oligogenic mode of inheritance might explain the existence of different NB loci genetically interacting to cause and/or modify the disease-phenotype.

Genome wide scan using homozygosity mapping and linkage analyses of a single pedigree with affective disorder suggests oligogenic inheritance.

The present study reports results from a genome scan on a family with bipolar affective disorder in which the parents are first cousins and four of the offsprings and one grandchild have affective disorder. The study searched for risk loci for affective disorder by searching for homozygous segments or more complex inherited loci using parametric and non-parametric multipoint linkage analysis. In addition dominant, multipoint, affecteds-only linkage analyses were performed as a supplement to previous analyses. On chromosomes 2q31.3, 10, 12q24, and 21q22.3 evidence for a risk locus was obtained by parametric and/or non-parametric linkage analyses and by haplotype sharing. As other studies have found significant or suggestive linkage to bipolar disorder in these chromosome regions this suggests that an oligogenic mode of inheritance is possible in this family involving at least some of the loci. Finally, the work discusses whether homozygosity mapping using parametric and non-parametric linkage analyses may be of value for complex diseases including rare subphenotypes of such disorders.