The genetic architecture of schizophrenia and bipolar disorder: identity by descent and exome sequencing in a family-based population sample

Schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic disorders, each with a prevalence of 1% in the population worldwide, and a consistent genetic overlap. Several genome-wide association studies (GWASs) have demonstrated that common polymorphisms can account only for half of the observed genetic variance in liability. Therefore, attention has turned towards the discovery of rare, high-penetrant risk variants. In this study a unique population sample is investigated, as all the patients have a common ancestry from a closed population with a high prevalence of SCZ and BPD. More than 150 familial cases are available for study. Considering these features, an enrichment of rare alleles can be hypothesized, facilitating their discovery in this sample. In a preliminary investigation, copy number variants (CNVs) were found to have a minor role for the disorders. Consequently, a novel approach has been developed to track loci shared by patients because inherited from common ancestors (IBD, identical by descent). A genome-wide map of the shared haplotype was obtained and then used to prioritize rare (MAF<1%) or novel variants from whole-exome sequencing of 17 patients. The results suggest that genes affected by these variants are selectively involved in axon guidance and synaptic transmission processes, both fundamental for neurosystem development and function. Moreover, the presence of identified variants was inferred in non-sequenced subjects on the basis of IBD map. Variants were shared across different families and some of them are segregating within multiple pedigrees, overall revealing a puzzle of loci coherent with the complex and polygenic architecture of the disorders. Among the candidate genes are GRM7 and GRM8, two metabotrobic glutamate receptors, and NCAM1 and NCAN, playing a role in neurite formation. Finally ,specific combinations of variants were detected in multiple patients from different pedigrees, possibly indicating interplays of alleles substantially increasing risk for the disorders. Concluding, a novel approach has been developed in this study, combining IBD mapping and whole-exome sequencing to investigate rare sequence variants in a closed population. Results provide some insights on the genetic architecture of SCZ and BPD, additionally proposing the involvement of axon guidance and synaptic transmission pathways in etiology. The identification of some candidate genes, then, could ultimately inform the search of new therapeutic targets for this common disorders with such a high burden for the society.La schizofrenia e il disturbo bipolare sono malattie genetiche complesse, ciascuna con una prevalenza dell’1% nella popolazione mondiale; una consistente sovrapposizione genetica è stata riportata per i due disordini. Numerosi studi di associazione genome-wide hanno dimostrato come polimorfismi comuni possano rendere conto solo di metà della varianza genetica attribuita ai due disordini. Di conseguenza, l’attenzione si è spostata sulla ricerca di varianti rare. In questo studio viene analizzato un campione di casi tutti provenienti da una comunità chiusa, in cui si registra una elevata prevalenza dei due disordini. Più di 150 casi familiari sono disponibili per lo studio. Considerando queste caratteristiche, è possibile ipotizzare un arricchimento di alleli rari, che ne facilita l’identificazione in questo campione. Inizialmente, è stato escluso un ruolo maggiore per le CNV (copy number variant). Di conseguenza, è stato sviluppato un nuovo approccio per identificare loci condivisi dai pazienti perché ereditati da ancestori comuni (IBD, identical by descent). Una mappa genome-wide degli aplotpi condivisi è stata ottenuta e poi utilizzata per prioritizzare varianti nuove o rare (MAF