Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive...

Area of Science:

• Genetics
• Neuroscience
• Genomic structural variation

Background:

• The 17q21.31 region, characterized by H1/H2 haplotypes and copy number variations (CNVs), is the strongest genetic risk locus for progressive supranuclear palsy (PSP).
• Understanding the role of these structural variations is crucial for elucidating PSP pathogenesis.

Purpose of the Study:

• To investigate the association between specific CNVs and structural forms within the 17q21.31 region and the risk of developing PSP.
• To analyze how these genetic variations influence gene expression and potentially contribute to PSP.

Main Methods:

• Whole genome sequencing data from 1684 PSP cases and 2392 controls were analyzed.
• Three large CNVs (α, β, and γ) and structural forms at 17q21.31 were identified and their association with PSP risk was assessed.
• Gene expression changes, including upregulation and downregulation of specific genes, were analyzed in response to γ duplication using RNA sequencing.

Main Results:

• Increased copy number of the gamma (γ) CNV was significantly associated with higher PSP risk (OR=1.10, P=0.0018).
• Specific H1 structural forms with additional γ copies (e.g., H1β1γ4) showed a markedly increased risk of PSP (OR=1.57).
• γ duplication led to altered expression of several genes, including ARL17B, LRRC37A/LRRC37A2, and NSFP1, with LRRC37A/LRRC37A2 predominantly affected in neuronal cells.

Conclusions:

• The copy number of γ at 17q21.31 is independently associated with PSP risk, even after accounting for H1/H2 haplotypes.
• The complex structural organization of the 17q21.31 region is a critical factor in assessing genetic susceptibility to PSP.
• These findings highlight the importance of considering CNVs and structural variations in the genetic architecture of PSP.