M103 - WHOLE GENOME SEQUENCING APPROACH TO IDENTIFY SUSCEPTIBILITY RARE VARIANTS IN A MULTIPLEX NUCLEAR FAMILY OF SCHIZOPHRENIA AND FOLLOW-UP RESEQUENCING

Abstract

Background Previous family, twins, and adoption studies have indicated substantial genetic contribution to schizophrenia. With the advent of Next-Generation Sequencing (NGS), a massively parallel throughput method that can sequence the whole human genome, it becomes feasible to search the whole genome for rare genetic variants specific to schizophrenia patients. A previous study among a large number of families of sib-pair co-affected with schizophrenia in Taiwan has revealed several linkage signals by incorporating several endophenotypes. This implies existence of genetic heterogeneity in schizophrenia. We hypothesized that there may be some rare but highly penetrant variants which segregate with schizophrenia within multiplex families. We hence postulated that multiplex nuclear families of schizophrenia may help identify certain inherited rare variants that can be used for replication in other multiplex families of schizophrenia. Methods We selected one high density schizophrenia family from Taiwan Schizophrenia Linkage Study (TSLS), which recruited schizophrenia patients and their first-degree relatives throughout Taiwan from 1998 to 2002. Whole genome sequencing was performed to sequence the whole genomes of a 5-member nuclear family, in which the mother and 2 children affected with schizophrenia, and the father and another child unaffected. Both dominant and recessive inheritance models were used to explore schizophrenia related genomic variations. The candidate variants selected from both dominant and recessive inheritance models warrant further replication in other multiplex families from TSLS. Results The results showed that total 1,147 variants were selected under recessive inheritance model. Whereas there were 39,330 variants selected under the dominant inheritance model. After comparing with the alleles listed in the 1000 Genomes Project, 1,626 variants that exhibited inheritance in the family but not seen in other known data bases were identified for those in accordance with dominant inheritance model. Besides, 3 non-synonymous exonic SNVs were resequenced in 5 individuals of the schizophrenia multiplex family by Sanger sequencing. One of these 3 non-synonymous exonic SNVs were replicated in other 7 multiplex families from TSLS with higher allele frequency within TSLS than Taiwan biobank. The other 2 non-synonymous exonic SNVs were private to this schizophrenia multiplex family. Discussion Our findings demonstrated the utility of NGS in identifying inherited rare genetic variants that are potentially associated with multiplex schizophrenia. Our use of a multiplex family can help exclude those variants due to typing error, or de novo mutations, and hence select those with high-penetrating susceptibility genetic variants for schizophrenia. In particular, one of the 3 non-synonymous exonic SNVs was identified in other 7 multiplex families from TSLS. The other 2 private non-synonymous exonic SNVs and remaining intronic SNVs require further evaluation in context of supporting data. This may lead to discovery if rare but inheritable susceptibility variants for schizophrenia and their underlying pathophysiology.