Whole Exome-Wide Association Identifies Rare Variants in GALNT9 Associated with Middle Eastern Papillary Thyroid Carcinoma Risk

SIMPLE SUMMARY: This study targeted the identification of rare variants in Middle Eastern papillary thyroid carcinoma (PTC) through an exome-wide association study. It was found that the GALNT9 gene was strongly associated with rare inactivating variants. Three genes (TRIM40, ARHGAP23, and SOX4) were associated with rare damaging variants (RDVs). Furthermore, seven genes (VARS1, ZBED9, PRRC2A, VWA7, TRIM31, TRIM40, and COL8A2) were associated with PTC risk. The study unveils some new genes to be potential candidates for PTC predisposition. ABSTRACT: Papillary thyroid carcinoma (PTC) is the commonest thyroid cancer. The majority of inherited causes of PTC remain elusive. However, understanding the genetic underpinnings and origins remains a challenging endeavor. An exome-wide association study was performed to identify rare germline variants in coding regions associated with PTC risk in the Middle Eastern population. By analyzing exome-sequencing data from 249 PTC patients (cases) and 1395 individuals without any known cancer (controls), GALNT9 emerged as being strongly associated with rare inactivating variants (RIVs) (4/249 cases vs. 1/1395 controls, OR = 22.75, p = 5.09 × 10(−5)). Furthermore, three genes, TRIM40, ARHGAP23, and SOX4, were enriched for rare damaging variants (RDVs) at the exome-wide threshold (p < 2.5 × 10(−6)). An additional seven genes (VARS1, ZBED9, PRRC2A, VWA7, TRIM31, TRIM40, and COL8A2) were associated with a Middle Eastern PTC risk based on the sequence kernel association test (SKAT). This study underscores the potential of GALNT9 and other implicated genes in PTC predisposition, illuminating the need for large collaborations and innovative approaches to understand the genetic heterogeneity of PTC predisposition.