publications

2024

1. 

   Genetic drivers and cellular selection of female mosaic X chromosome loss

   Aoxing Liu, Giulio Genovese, Yajie Zhao, and 38 more authors

   Nature, Jul 2024

   Abs

   Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

2. 

   Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease

   Yajie Zhao, Maria Chukanova, Katherine A. Kentistou, and 31 more authors

   Nature Genetics, Apr 2024

   Abs

   Abstract Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes ( BSN and APBA1 ) with effects substantially larger than those of well-established obesity genes such as MC4R . In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

3. 

   Population scale whole genome sequencing provides novel insights into cardiometabolic health

   Yajie Zhao, Sam Lockhart, Jimmy Liu, and 14 more authors

   Jun 2024

   Abs

   In addition to its coverage of the non-coding genome, whole genome sequencing (WGS) may better capture the coding genome than exome sequencing. We sought to exploit this and identify novel rare, protein-coding variants associated with metabolic health in newly released WGS data (N=708,956) from the UK Biobank and All of Us studies. Identified genes highlight novel biological mechanisms, including protein truncating variants (PTVs) in the DNA double-strand break repair gene RIF1 that have a substantial effect on body mass index (BMI, 2.66 kg/m2, s.e. 0.43, P = 3.7×10-10). 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. Our study demonstrates that large-scale WGS provides novel mechanistic insights into human metabolic phenotypes through improved capture of coding sequences.

2023

1. 

   Shared and distinct genetic etiologies for different types of clonal hematopoiesis

   Derek W. Brown, Liam D. Cato, Yajie Zhao, and 12 more authors

   Nature Communications, Sep 2023

2022

1. 

   Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution

   Mine Koprulu, Yajie Zhao, Eleanor Wheeler, and 27 more authors

   The Journal of Clinical Endocrinology & Metabolism, Mar 2022

   Abs

   Abstract Context Biological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking predominantly noncoding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss of function (LoF) would be of most therapeutic benefit. Objective This work aimed to identify genes/proteins involved in determining fat distribution. Methods We combined the power of genome-wide analysis of array-based rare, nonsynonymous variants in 450 562 individuals in the UK Biobank with exome-sequence-based rare LoF gene burden testing in 184 246 individuals. Results The data indicate that the LoF of 4 genes (PLIN1 [LoF variants, P = 5.86 × 10–7], INSR [LoF variants, P = 6.21 × 10–7], ACVR1C [LoF + moderate impact variants, P = 1.68 × 10–7; moderate impact variants, P = 4.57 × 10–7], and PDE3B [LoF variants, P = 1.41 × 10–6]) is associated with a beneficial effect on body mass index–adjusted waist-to-hip ratio and increased gluteofemoral fat mass, whereas LoF of PLIN4 (LoF variants, P = 5.86 × 10–7 adversely affects these parameters. Phenotypic follow-up suggests that LoF of PLIN1, PDE3B, and ACVR1C favorably affects metabolic phenotypes (eg, triglycerides [TGs] and high-density lipoprotein [HDL] cholesterol concentrations) and reduces the risk of cardiovascular disease, whereas PLIN4 LoF has adverse health consequences. INSR LoF is associated with lower TG and HDL levels but may increase the risk of type 2 diabetes. Conclusion This study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counterintuitive insight into the potential consequences of targeting these molecules therapeutically.

2. 

   Detection and characterization of male sex chromosome abnormalities in the UK Biobank study

   Yajie Zhao, Eugene J. Gardner, Marcus A. Tuke, and 17 more authors

   Genetics in Medicine, Sep 2022

2021

1. 

   GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health

   Yajie Zhao, Stasa Stankovic, Mine Koprulu, and 10 more authors

   Nature Communications, Jul 2021

   Abs

   Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes—CHEK2 and GIGYF1—reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04–11.81], p = 1.3 × 10−10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51–10.61], p = 1.8 × 10−12), 4 kg higher fat mass (p = 1.3 × 10−4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10−4) and 4.5 kg lower handgrip strength (p = 4.7 × 10−7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.