Damaging missense variants in<i>IGF1R</i>implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes

Gardner, Eugene J.; Kentistou, Katherine A.; Stankovic, Stasa; Lockhart, Samuel; Wheeler, Eleanor; Day, Felix R.; Kerrison, Nicola D.; Wareham, Nick; Langenberg, Claudia; O’Rahilly, Stephen; Ong, Ken K; Perry, John R. B.

doi:10.1101/2022.03.26.22272972

Cited by 16 publications

(13 citation statements)

References 76 publications

(110 reference statements)

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“…Prior to performing association tests, we performed quality control on provided sequencing data as previously described. 61…”

Section: Methodsmentioning

confidence: 99%

“…Prior to performing association tests, we performed quality control on provided sequencing data as previously described. 61 We utilized the ENSEMBL Variant Effect Predictor (VEP) v104 62 to annotate variants on the autosomal and X chromosomes. VEP was run with default settings, the "everything" flag, and the LOFTEE plugin.…”

Section: Rare Variants Gene-burden Test For Loy In Uk Biobankmentioning

confidence: 99%

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Shared and distinct genetic etiologies for different types of clonal hematopoiesis

Brown

Cato

Zhao

et al. 2022

Preprint

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Clonal hematopoiesis (CH) — age-related expansion of mutated hematopoietic clones — can differ in frequency and cellular fitness. Descriptive studies have identified a spectrum of events (coding mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs) and loss of sex chromosomes), some of which have been associated with disease risk. Co-existence of different CH events raises key questions as to their origin, selection, and impact. Analyses of sequence and genotype array data in up to 482,378 individuals from UK Biobank revealed shared genetic architecture across different types of CH. We observed co-occurrence of CHIP and mCAs with co-localization at TET2, DNMT3A and JAK2, in which CHIP precedes mCA acquisition. CH types are associated with cellular differentiation, DNA repair, and cell cycle regulation pathways, which can drive clonal expansion and reduce telomere length. Insights into the shared architecture of CH could improve detection and prevention of CH-related outcomes.

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“…Prior to performing association tests, we performed quality control on provided sequencing data as previously described. 61…”

Section: Methodsmentioning

confidence: 99%

Section: Rare Variants Gene-burden Test For Loy In Uk Biobankmentioning

confidence: 99%

Shared and distinct genetic etiologies for different types of clonal hematopoiesis

Brown

Cato

Zhao

et al. 2022

Preprint

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“…To identify rare germline variants (minor allele frequency (MAF) < 0.1%) associated with the risk of detectable mLOX, we performed gene-burden tests on chromosomes 1-22 and X in 226,125 UKBB female participants with WES data available. We performed WES data pre-processing and quality control following Gardner et al 76 . We annotated variants using the ENSEMBL Variant Effect Predictor (VEP) v104 77 and defined protein-truncating variants (PTVs) as high-confidence (HC, as defined by LOFTEE) stop gained, splice donor/acceptor, and frameshift consequences.…”

Section: Gene-burden Test For Rare Variants Causing Detectable Mloxmentioning

confidence: 99%

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

Zhao

Pirinen

et al. 2023

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Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants in FBXO10 which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.

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“…The gene-set burden tests were performed by extending an association testing workflow of applets designed for the UK Biobank RAP for single genes to gene-sets. The RAP association workflow is described in detail in Gardner et al , 2022 52 . In total, we conducted four gene-set burden tests, collapsing variants and genes into the following categories: (1 AD only genes (N=38), (2) AR genes (N=57), (3) genes with both AD and AR inheritance (N=2), and (4) all 105 genes ( Supplementary Table 11 ).…”

Section: Methodsmentioning

confidence: 99%

Monogenic causes of Premature Ovarian Insufficiency are rare and mostly recessive

Shekari

Stankovic

Gardner

et al. 2022

Preprint

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Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported natural menopause under the age of 40. In the largest study of POI to date, we found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes we were able to rule out even modest penetrance, with 99.9% (13,699/13,708) of all identified protein truncating variants found in reproductively healthy women. We found evidence of novel haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P=1.59*10-6) and SOHLH2 (3.48 years earlier menopause, P=1.03*10-4). Collectively our results suggest that for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. We suggest that the majority of POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic studies, and genetic counselling for families affected by POI.

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Damaging missense variants inIGF1Rimplicate a role for IGF-1 resistance in the aetiology of type 2 diabetes

Cited by 16 publications

References 76 publications

Shared and distinct genetic etiologies for different types of clonal hematopoiesis

Shared and distinct genetic etiologies for different types of clonal hematopoiesis

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

Monogenic causes of Premature Ovarian Insufficiency are rare and mostly recessive

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