De novo variation in bipolar disorder

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Bipolar disorder (BD) is a common, highly heritable psychiatric disorder affecting 1-2% of the global population.
• While common genetic variations have been studied, a significant portion of BD's heritability remains unexplained, potentially due to rare genetic variations.
• The de novo paradigm, focusing on newly arisen variants, offers a unique approach to identifying highly pathogenic mutations in BD.

Purpose of the Study:

• To identify newly arisen (de novo) genetic variants associated with bipolar disorder (BD) using whole genome sequencing.
• To investigate the role of rare genetic variation, particularly loss-of-function (LoF) and missense damaging variants, in the genetic architecture of BD.
• To explore the enrichment of these variants in specific gene sets, such as constrained genes, postsynaptic density (PSD) genes, and the phosphoinositide (PI) pathway.

Main Methods:

• Whole genome sequencing was performed on 97 trios of Ashkenazi Jewish descent with simplex BD (no family history) and early onset.
• De novo variants were identified and combined with data from 79 previously published BD trios.
• Statistical analyses, including Bonferroni correction, were used to assess variant enrichment in specific genes, pathways, and to evaluate polygenic risk transmission.

Main Results:

• A total of 6882 de novo variants were identified, including 107 within protein-coding genes.
• Combined analysis revealed 20 loss-of-function (LoF) and 77 missense damaging de novo variants in BD.
• These variants were significantly enriched in constrained genes and genes within the postsynaptic density (PSD), with notable enrichment in the phosphoinositides (PI) pathway (p=4.2×10⁻⁶).

Conclusions:

• The findings support the de novo paradigm as a significant contributor to the genetic architecture of bipolar disorder (BD).
• Rare variations in constrained genes, PSD genes, and the PI pathway are implicated in the etiology of BD.
• This research highlights the importance of investigating rare genetic variants alongside common ones for a comprehensive understanding of BD's heritability.