Copy number variants in lipid metabolism genes are associated with gallstones disease in men

Abstract

Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10-20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size > 100 kb, frequency < 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 × 10-4 ; OR = 2.76; CI 95% = 1.53-4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.

Fully exploiting SNP arrays: a systematic review on the tools to extract underlying genomic structure

“…In particular, CNV genotyping was crucial in studies involving diseases such as schizophrenia [ 216 , 217 ], bipolar disorder [ 216 ], Parkinson’s disease [ 218 ], Autism Spectrum Disorder [ 219 ] and attention deficit hyperactivity disorder [ 220 ]. Other CNVs studies included different outcomes such as HBV [ 221 , 222 ], autophagy [ 223 ], gallstones disease [ 224 ], vesicoureteral reflux [ 225 ], esotropia [ 226 ], cheap screenings for primary immunodeficiency [ 227 ] and COVID-19 potential targets [ 228 ]. For these studies, PennCNV was the most popular, followed by Nexus Copy Number, Birdsuite and QuantiSNP.…”

CNest: A Novel Copy Number Association Discovery Method Uncovers 862 New Associations from 200,629 Whole Exome Sequence Datasets in the UK Biobank

“…Genetic variation of UGT1A genes has been associated with disorders of bilirubin metabolism including Gilbert's syndrome by multiple previous SNP GWAS studies (120,121) with, for example, very strong association signal at UGT1A10 for the intron variant rs6742078 (2_233763993_G_T) (122). This specific SNP has also been linked to other lipid metabolism disorders such as Gallstones Disease (GSD) (123) and although studies looking at CNV burden analysis of lipid metabolism genes has shown a significant enrichment in GSD cases none of those associations could be attributed to any single gene (124). Here we provide novel CNV associations at UGT1A genes with a direct link to bilirubin metabolism that could be an important risk factor for lipid metabolism related disorders.…”

Identification of Intestinal Microbial Community in Gallstone Patients with Metagenomic Next-Generation Sequencing

“…The cholesterol gallstone is the most familiar type of GD in cholecystectomy [ 2 ]. The prevalence of GD is extremely high in Western countries with the rate of about 10~20% [ 3 ]. Nowadays, GD has become more and more prevalent in China, ranging from 10 to 15% [ 4 ].…”

“…(2) The functions of differential gut microbiota in GD patients. (3) The relationship between intestinal microbiota and traditional biochemical markers in patients with cholelithiasis. (4) The potential mechanism of how the intestinal microbial community affects the formation of gallstones.…”