Abstract
We investigated the genetic causes of major mental disorders (MMDs) including schizophrenia, bipolar disorder I, major depressive disorder and attention deficit hyperactive disorder, in a large family pedigree from Alpujarras, South of Spain, a region with high prevalence of psychotic disorders. We applied a systematic genomic approach based on karyotyping (n = 4), genotyping by genome-wide SNP array (n = 34) and whole-genome sequencing (n = 12). We performed genome-wide linkage analysis, family-based association analysis and polygenic risk score estimates. Significant linkage was obtained at chromosome 9 (9q33.1–33.2, LOD score = 4.11), a suggestive region that contains five candidate genes ASTN2, BRINP1, C5, TLR4 and TRIM32, previously associated with MMDs. Comprehensive analysis associated the MMD phenotype with genes of the immune system with dual brain functions. Moreover, the psychotic phenotype was enriched for genes involved in synapsis. These results should be considered once studying the genetics of psychiatric disorders in other families, especially the ones from the same region, since founder effects may be related to the high prevalence.
Highlights
Psychiatric disorders aggregate in families and their predisposition involve a complex, polygenic and pleiotropic genetic architecture[1,2,3]
In this study we have applied a systemic genomic approach to uncover the genomic architecture of a large lineage, with 41 individuals affected of major mental disorders (MMDs) in the last three generations, 27 of which have been diagnosed with psychotic disorders
A large multigenerational family of Southern Spanish origin with high prevalence of mental disorder was recruited between the Psychiatry ward of the University Hospital Son Espases (HUSE) of the Balearic Islands and the Health Center of El Ejido
Summary
Psychiatric disorders aggregate in families and their predisposition involve a complex, polygenic and pleiotropic genetic architecture[1,2,3]. In this study we have applied a systemic genomic approach to uncover the genomic architecture of a large lineage, with 41 individuals affected of MMD in the last three generations, 27 of which have been diagnosed with psychotic disorders. This family is from a region of southern Spain, the Alpujarras, known to be a hotspot for psychiatric diseases, with a prevalence of 7.8%28, almost double of that from the rest of the country, suggestive of being due to founding genetic events
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