Predicted loss of function alleles in Bassoon (BSN) are associated with obesity

Abstract

Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with log10-p value of 11.78 in the UK biobank cohort. The association was replicated in the All of Us whole genome sequencing data. Additionally, we have identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity at Columbia University. Like the individuals identified in the UKBB and All of us Cohorts, these individuals have no history of neurobehavioral or cognitive disability. Heterozygosity for pLoF BSN variants constitutes a new etiology for obesity.

Population scale whole genome sequencing provides novel insights into cardiometabolic health

“…(Figure 1 and Supplementary Table 1) The only overlapping association between the two traits was with PTVs in UBR3 . Our WGS analysis confirmed previously reported gene associations using WES for BMI including PTVs and damaging missense variants in MC4R , UBR2 , SLTM and PCSK1 , BSN , APBA1 and PTPRG 8,10,13,14 . Our WGS analysis also confirmed previously reported gene associations using WES for T2D including PTVs in GCK , HNF1A , GIGYF1 and TNRC6B , and missense variants with REVEL >= 0.7 in IGF1R 11,13 .…”

“…At the seven genes that have not been previously implicated via population-scale studies for T2D, PTVs conferred higher risk for T2D: IRS2 (OR per allele =6.4, 95% CI [3.7-11.3], P = 9.9 × 10 -14 , carrier n = 58, 34% case prevalence among carriers) - encoding a key adaptor molecule in the insulin-signaling cascade, UBR3 (OR =3.4, 95% CI [2.1-5.2], P = 6.1 × 10 -9 , carrier n = 115, 23% case prevalence) - encoding a component of N-terminal acetyltransferase complexes 19 , NAA15 (OR =5.3, 95% CI [2.6-10.6], P = 1.2 × 10 -7 , carrier n = 39, 31% case prevalence) and RMC1 (OR =2.7, 95% CI [1.8-4.2], P = 3.4 × 10 -7 , carrier n = 138, 20% case prevalence) - encoding part of a protein complex critical for lysosomal trafficking and autophagy 20,21 . (Supplementary Table 4) Our missense mask also identified associations with IP6K1 (OR =3.6, 95% CI [2.2-6.0], P = 8.5 × 10 -9 , carrier n = 84, 26% case prevalence) - encoding inositol phosphokinase, the known MODY gene HNF4A (OR =1.5, 95% CI [1.3-1.8], P = 3.1 × 10 -9 , carrier n = 1,386, 13% case prevalence), and UBB (OR =3.7, 95% CI [2.1-6.4], P = 5.8 × 10 -7 , carrier n = 66, 26% case prevalence) - encoding ubiquitin.…”

“…Previous large-scale WES studies have identified several genes harbouring rare protein coding variants of large effect for these traits [8][9][10][11][12] including examples where heterozygous loss of function either increases (e.g. GIGYF1 for T2D 13 , BSN for obesity 9,14 ) or decreases the risk of disease (e.g. MAP3K15 for T2D 12 , GPR75 for obesity 8 ).…”

“…UBR3 is an intriguing example where PTVs independently increase BMI and type 2 diabetes (T2D) risk. Furthermore, PTVs in IRS2 have a substantial effect on T2D (OR 6.4 [3.7-11.3], P = 9.9×10 -14 , 34% case prevalence among carriers) and were unexpectedly also associated with chronic kidney disease independent of diabetes status, suggesting an important role for IRS-2 in maintaining renal health. We identified genetic evidence of functional heterogeneity in IRS1 and IRS2 , suggesting a greater role for IRS-1 in mediating the growth promoting effects of insulin and IGF-I, while IRS-2 has a greater impact on glucose homeostasis likely through its actions in the pancreatic islet and insulin target tissues.…”