Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of ...drug targets in humans through protein quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques-the aptamer-based SomaScan
v4 assay and the antibody-based Olink assays-to systematically assess phenotypic consequences of hundreds of pQTLs discovered for 871 protein targets across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein-phenotype connections, 36.3% of which were only seen with one of the two platforms suggesting that both techniques capture distinct aspects of protein biology. We further highlight discordance of genetically predicted effect directions between assays, such as for PILRA and Alzheimer's disease. Our results showcase the synergistic nature of these technologies to better understand and identify disease mechanisms and provide a benchmark for future cross-platform discoveries.
Mapping the proteo-genomic convergence of human diseases Pietzner, Maik; Wheeler, Eleanor; Carrasco-Zanini, Julia ...
Science (American Association for the Advancement of Science),
2021-Nov-12, Letnik:
374, Številka:
6569
Journal Article
Recenzirano
Odprti dostop
Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to ...create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries.
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
). 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
), 4 kg higher fat mass (p = 1.3 × 10
), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10
) and 4.5 kg lower handgrip strength (p = 4.7 × 10
) 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.
Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 ...controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.
Fraser syndrome is characterized by cryptophthalmos, syndactyly and other autopod defects, and abnormalities of the respiratory and urogenital tracts. Biallelic variants in GRIP1 can cause Fraser ...syndrome 3 (FRASRS3), and five unrelated FRASRS3 cases have been reported to date. Four cases are fetuses with homozygous truncating variants. The remaining case is an almost 9‐year‐old Turkish girl compound heterozygous for a truncation variant and a possibly frame‐shift intragenic deletion. We present a 15.5‐year old Pakistani boy with homozygous truncating variant c.1774C>T (p.Gln592Ter). Of the hallmarks of the disease, the boy has cryptophthalmia, midface retrusion, very low anterior hairline, hair growth on temples extending to the supraorbital line and also on alae nasi, agenesis of right kidney, and cutaneous syndactyly of fingers and toes but no symptoms in any other organs, including lungs, anorectal system, genitalia, and umbilical system. This case is the oldest known individual with FRASRS3, and our findings show that a homozygous GRIP1 truncating variant can manifest with a non‐lethal phenotype than in the reported cases with such variants, expanding the phenotypic and mutational spectrum of GRIP1.
We present a Pakistani kinship afflicted with a syndrome with features including short stature, reduced sitting height, orofacial symptoms including prominent forehead and thick eyebrows, short and ...broad thorax, and variable features such as long philtrum, short broad neck, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Phenotypic variation even within different sibships was considerable. The unique combination of the phenotypic characteristics prompted us to determine the shared homozygosity regions in patient genomes and the pathogenic variants by next generation technologies like single nucleotide polymorphism (SNP) genotyping and whole exome sequencing (WES). Through these analyses, we detected homozygous OBSL1 c.848delG (p.Gly283AlafsTer54) as the causal variant. Biallelic variants in OBSL1 are known to cause Three M Syndrome 2 (3M2), a rare disorder of growth retardation with characteristic facial dysmorphism and musculoskeletal abnormalities. Affected members of the family do not have the 3M2 hallmark features of dolichocephaly, hypoplastic midface, anteverted nares, low nasal bridge, pectus excavatum, sacral hyperlordosis, spina bifida occulta, anterior wedging of thoracic vertebrae, prominent heels, and prominent talus. Moreover, they have some variable features not typical for the syndrome such as round face, disproportionate short stature, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Our study facilitated genetic diagnosis in the family, expanded the clinical phenotype for 3M2, and unraveled the considerable clinical variation within the same kinship. We conclude that unbiased molecular analyses such as WES should be more integrated into healthcare, particularly in populations with high parental consanguinity, given the potential of such analyses to facilitate diagnosis.
We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two consanguineous Pakistani families. This ...atypical PC is characterized by an unusual combination of pachyonychia, plantar keratoderma, folliculitis, alopecia, sparse eyebrows, dental anomalies and variable acanthosis nigricans of neck, dry skin, palmoplantar hyperhidrosis, recurrent blisters on soles and/or arms, rough sparse hair on scalp and keratosis pilaris. By exome sequencing we detected homozygous KRT17 c.281G>A (p.(Arg94His)) in affected individuals, and linkage mapping indicated a single locus. Heterozygous variants in KRT17 cause PC2 (PC-K17) with main characteristics of pachyonychia, subungual keratosis, palmoplantar keratoderma, hyperhidrosis, oral leukokeratosis and epidermal cysts, or steatocystoma multiplex, both with dominant inheritance. The causative variant has been reported in heterozygous state in a family afflicted with severe steatocystoma multiplex and in a sporadic PC2 case, and thus we also define a third phenotype related to the variant. Both exome sequencing and linkage mapping demonstrated recessive inheritance whereas Sanger sequencing indicated heterozygosity for the causal variant, reiterating caution for simple targeted sequencing for genetic testing. Testing parents for variants found in sibs could uncover recessive inheritance also in other KRT genes.
In a consanguineous Pakistani kinship afflicted with mild to moderate intellectual disability (ID), mild lissencephaly, brain atrophy and skeletal anomalies, we detected homozygous CRADD c.2T > G ...(p.Met1?) and USP44 c.873_886delinsT (p.Leu291Phefs*8), two good candidates 1.85-Mb apart that segregated with the disorder. Biallelic damaging variants in CRADD cause recessive mental retardation-34 (MRT34; MIM 614499) with mild to moderate ID, “thin” lissencephaly, and variable megalencephaly and seizures. For USP44, only a single ID family has been reported with a homozygous deleterious variant, which is the same as the variant we detected. In affected individuals we present, at ages 29–32 years, clinical findings are similar yet not fully concordant with phenotypes for either gene considering the skeletal findings, and ID is not as severe as would be expected for defects in two genes with additive effect. Some variable CRADD-related features such as language impairment and seizures are not observed in the presented family. The presence of the two variants in the family is a very rare example of familial linked homozygous variants, and whether the damaging USP44 variant contributed to the disease in the family we present is not clear. As for the skeletal findings, facial dysmorphism and digestive problems, we did not find a candidate variant. This study is an example of both clinical variation and difficulty in variant detection and evaluation. Our findings highlight that even an extensive exome sequence analysis can fail to fully uncover the complex molecular basis of a syndrome even if potentially causative variants are identified.
Broad-capture proteomic technologies have the potential to improve disease prediction, enabling targeted prevention and management, but studies have so far been limited to very few selected diseases ...and have not evaluated predictive performance across multiple conditions. We aimed to evaluate the potential of serum proteins to improve risk prediction over and above health-derived information and polygenic risk scores across a diverse set of 24 outcomes.
We designed multiple case-cohorts nested in the EPIC-Norfolk prospective study, from participants with available serum samples and genome-wide genotype data, with more than 32 974 person-years of follow-up. Participants were middle-aged individuals (aged 40–79 years at baseline) of European ancestry who were recruited from the general population of Norfolk, England, between March, 1993 and December, 1997. We selected participants who developed one of ten less common diseases within 10 years of follow-up; we also subsampled a randomly drawn control subcohort, which also served to investigate 14 more common outcomes (n>70), including all-cause premature mortality (death before the age of 75 years; case numbers 71–437; controls 608–1556). Individuals were excluded from the current study owing to failed genotyping or proteomic quality control, relatedness, or missing information on age, sex, BMI, or smoking status. We used a machine learning framework to derive sparse predictive protein models for the onset of the the 23 individual diseases and all-cause premature mortality, and to derive a single common sparse multimorbidity signature that was predictive across multiple diseases from 2923 serum proteins.
Participants who developed one of ten less common diseases within 10 years of follow-up included 482 women and 507 men, with a mean age at baseline of 64·56 years (8·08). The random subcohort included 990 women and 769 men, with a mean age of 58·79 years (9·31). As few as five proteins alone outperformed polygenic risk scores for 17 of 23 outcomes (median dfference in concordance index C-index 0·13 0·10–0·17) and improved predictive performance when added over basic patient-derived information models for seven outcomes, achieving a median C-index of 0·82 (IQR 0·77–0·82). This included diseases with poor prognosis such as lung cancer (C-index 0·85 +/− cross-validation error 0·83–0·87), for which we identified unreported biomarkers such as C-X-C motif chemokine ligand 17. A sparse multimorbidity signature of ten proteins improved prediction across seven outcomes over patient-derived information models, achieving performances (median C-index 0·81 IQR 0·80–0·82) similar to those of disease-specific signatures.
We show the value of broad-capture proteomic biomarker discovery studies across multiple diseases of diverse causes, pointing to those that might benefit the most from proteomic approaches, and the potential to derive common sparse biomarker panels for prediction of multiple diseases at once. This framework could enable follow-up studies to explore the generalisability of proteomic models and to benchmark these against clinical assays, which are required to understand the translational potential of these findings.
Medical Research Council, Health Data Research UK, UK Research and Innovation–National Institute for Health and Care Research, Cancer Research UK, and Wellcome Trust.
The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome KS) and 47,XYY, and characterize their risks of adverse health outcomes.
We analyzed ...genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data.
Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio RR = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = –3.8 nmol/L, all P < 2 × 10–8), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P < 7 × 10–6).
KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking.
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