Molecular validation of the schizophrenia spectrum

Area of Science:

• Psychiatric Genetics
• Schizophrenia Spectrum Disorders
• Molecular Psychiatry

Background:

• Family and adoption studies suggest genetic aggregation of personality and psychotic disorders in schizophrenia families.
• The hypothesis of a shared genetic basis across the schizophrenia spectrum requires validation using molecular genetic data.

Purpose of the Study:

• To validate the schizophrenia spectrum using polygenic risk scores derived from genome-wide association studies (GWAS).
• To assess the genetic liability across different diagnostic categories within schizophrenia spectrum disorders.

Main Methods:

• Utilized polygenic risk scores from the Psychiatric GWAS Consortium (PGC) applied to relatives in the Irish Study of High-Density Schizophrenia Families (ISHDSF).
• Constructed individual polygenic risk scores using genome-wide SNP data from affected and unaffected relatives.
• Compared mean polygenic scores between ISHDSF participants and ethnically matched population controls.

Main Results:

• Schizophrenia polygenic scores varied significantly across diagnostic categories, being highest in narrow schizophrenia spectrum diagnoses.
• Relatives across all affected groups, including those without psychiatric diagnoses, exhibited significantly higher polygenic scores than controls.
• Intermediate, broad, and very broad schizophrenia spectrum categories showed intermediate polygenic scores.

Conclusions:

• The enrichment of polygenic risk variants in relatives supports a continuous liability distribution for schizophrenia spectrum disorders.
• Aggregate common risk alleles validate a genetic basis for the schizophrenia spectrum.
• Nonpsychotic family members of schizophrenia patients carry significantly more polygenic risk variants than the general population.