Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth

We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions

UK Biobank is a population-based cohort of half a million participants aged 40–69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world’s largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future direction

Handedness GWAS summary statistic files

GWAS summary data for Wiberg et al, Brain 2019

Handedness GWAS summary statistic files

GWAS summary data for Wiberg et al, Brain 2019

The genetic architecture of carpal tunnel syndrome

Carpal tunnel syndrome (CTS) is a debilitating disease of the hand caused by compression of the median nerve within an anatomical tunnel in the wrist. It is a common disease with an estimated population prevalence of 5–10%. Symptoms include pain, paraesthesia, and numbness of the hand, and thenar weakness that ultimately leads to functional impairment. Many patients require surgery to relieve the pressure on the median nerve; although surgery is successful in the majority of patients, a significant sub-group experiences persistent or recurrent symptoms. Despite being such a common disease, the pathophysiology of CTS is poorly understood, and even less is known about the genetic contribution to the disease. The heritability of CTS is estimated at 0.46, and approximately one-third of patients report a family history. CTS is a complex disease, where genetic and non-genetic factors interact to affect overall phenotypic expression. The current best method for interrogating a complex disease is with a genome-wide association study (GWAS). I present the findings from the first ever genome-wide association of CTS, undertaken in over 12,000 CTS cases and nearly 400,000 controls from UK Biobank. The GWAS uncovered 16 genomic loci significantly associated with CTS. In silico analyses of the GWAS data using an array of bioinformatic tools discovered genetic variants at the GWAS-associated loci with strong evidence of functionality, and implicated several biologically plausible genes in CTS pathogenesis, including EFEMP1, ADAMTS17 and ADAMTS10. These genes were strongly enriched for biological pathways and gene ontologies pertaining to the extracellular matrix. These analyses were followed by epidemiological investigations in UK Biobank, including Mendelian randomisation to assess the causal role of various putative risk factors on CTS aetiology. These studies identified a causal role for shorter height, greater BMI, and younger age at menarche in the development of CTS. In the final results chapter, a polygenic risk score was constructed to validate the genetic variants discovered in the GWAS in a small cohort of deeply phenotyped CTS patients. RNA- sequencing performed in tenosynovial tissues collected from these patients demonstrated high expression of the candidate genes that were identified in the GWAS. Several GWAS loci demonstrated genotype-specific expression of these genes, providing evidence of functionality. This work represents the first use of big data and computational genetics to delineate the genetic basis of CTS. I have provided evidence for a robust genetic architecture underlying CTS and have identified several biologically plausible candidate genes that contribute to its pathophysiology. The insights into the aetiology of CTS have revealed testable functional hypotheses and potential therapeutic avenues for further research.</p

The genetic architecture of carpal tunnel syndrome

Carpal tunnel syndrome (CTS) is a debilitating disease of the hand caused by compression of the median nerve within an anatomical tunnel in the wrist. It is a common disease with an estimated population prevalence of 5â10%. Symptoms include pain, paraesthesia, and numbness of the hand, and thenar weakness that ultimately leads to functional impairment. Many patients require surgery to relieve the pressure on the median nerve; although surgery is successful in the majority of patients, a significant sub-group experiences persistent or recurrent symptoms. Despite being such a common disease, the pathophysiology of CTS is poorly understood, and even less is known about the genetic contribution to the disease. The heritability of CTS is estimated at 0.46, and approximately one-third of patients report a family history. CTS is a complex disease, where genetic and non-genetic factors interact to affect overall phenotypic expression. The current best method for interrogating a complex disease is with a genome-wide association study (GWAS). I present the findings from the first ever genome-wide association of CTS, undertaken in over 12,000 CTS cases and nearly 400,000 controls from UK Biobank. The GWAS uncovered 16 genomic loci significantly associated with CTS. In silico analyses of the GWAS data using an array of bioinformatic tools discovered genetic variants at the GWAS-associated loci with strong evidence of functionality, and implicated several biologically plausible genes in CTS pathogenesis, including EFEMP1, ADAMTS17 and ADAMTS10. These genes were strongly enriched for biological pathways and gene ontologies pertaining to the extracellular matrix. These analyses were followed by epidemiological investigations in UK Biobank, including Mendelian randomisation to assess the causal role of various putative risk factors on CTS aetiology. These studies identified a causal role for shorter height, greater BMI, and younger age at menarche in the development of CTS. In the final results chapter, a polygenic risk score was constructed to validate the genetic variants discovered in the GWAS in a small cohort of deeply phenotyped CTS patients. RNA- sequencing performed in tenosynovial tissues collected from these patients demonstrated high expression of the candidate genes that were identified in the GWAS. Several GWAS loci demonstrated genotype-specific expression of these genes, providing evidence of functionality. This work represents the first use of big data and computational genetics to delineate the genetic basis of CTS. I have provided evidence for a robust genetic architecture underlying CTS and have identified several biologically plausible candidate genes that contribute to its pathophysiology. The insights into the aetiology of CTS have revealed testable functional hypotheses and potential therapeutic avenues for further research.</p

Varicose veins GWAS summary statistics

Summary statistics for discovery GWAS of 22,473 varicose veins cases and 379,183 non-varicose veins controls in UK Biobank. Related publication: Ahmed W. et al., Nature Communications, 2022. SNP = SNP name CHR = Chromosome number BP = Genomic position (GRCh37) ALLELE1 = effect allele ALLELE0 = non-effect allele A1FREQ = frequency of allele A INFO = INFO score for imputed SNPs BETA = beta coefficient SE = standard error PVAL = p-valu

The Pathophysiological Significance of Fibulin-3

Fibulin-3 (also known as EGF-containing fibulin extracellular matrix protein 1 (EFEMP1)) is a secreted extracellular matrix glycoprotein, encoded by the EFEMP1 gene that belongs to the eight-membered fibulin protein family. It has emerged as a functionally unique member of this family, with a diverse array of pathophysiological associations predominantly centered on its role as a modulator of extracellular matrix (ECM) biology. Fibulin-3 is widely expressed in the human body, especially in elastic-fibre-rich tissues and ocular structures, and interacts with enzymatic ECM regulators, including tissue inhibitor of metalloproteinase-3 (TIMP-3). A point mutation in EFEMP1 causes an inherited early-onset form of macular degeneration called Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). EFEMP1 genetic variants have also been associated in genome-wide association studies with numerous complex inherited phenotypes, both physiological (namely, developmental anthropometric traits) and pathological (many of which involve abnormalities of connective tissue function). Furthermore, EFEMP1 expression changes are implicated in the progression of numerous types of cancer, an area in which fibulin-3 has putative significance as a therapeutic target. Here we discuss the potential mechanistic roles of fibulin-3 in these pathologies and highlight how it may contribute to the development, structural integrity, and emergent functionality of the ECM and connective tissues across a range of anatomical locations. Its myriad of aetiological roles positions fibulin-3 as a molecule of interest across numerous research fields and may inform our future understanding and therapeutic approach to many human diseases in clinical settings

The Pathophysiological Significance of Fibulin-3

Fibulin-3 (also known as EGF-containing fibulin extracellular matrix protein 1 (EFEMP1)) is a secreted extracellular matrix glycoprotein, encoded by the EFEMP1 gene that belongs to the eight-membered fibulin protein family. It has emerged as a functionally unique member of this family, with a diverse array of pathophysiological associations predominantly centered on its role as a modulator of extracellular matrix (ECM) biology. Fibulin-3 is widely expressed in the human body, especially in elastic-fibre-rich tissues and ocular structures, and interacts with enzymatic ECM regulators, including tissue inhibitor of metalloproteinase-3 (TIMP-3). A point mutation in EFEMP1 causes an inherited early-onset form of macular degeneration called Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). EFEMP1 genetic variants have also been associated in genome-wide association studies with numerous complex inherited phenotypes, both physiological (namely, developmental anthropometric traits) and pathological (many of which involve abnormalities of connective tissue function). Furthermore, EFEMP1 expression changes are implicated in the progression of numerous types of cancer, an area in which fibulin-3 has putative significance as a therapeutic target. Here we discuss the potential mechanistic roles of fibulin-3 in these pathologies and highlight how it may contribute to the development, structural integrity, and emergent functionality of the ECM and connective tissues across a range of anatomical locations. Its myriad of aetiological roles positions fibulin-3 as a molecule of interest across numerous research fields and may inform our future understanding and therapeutic approach to many human diseases in clinical settings

The relationship between body mass index and the risk of development of Dupuytren's disease: a Mendelian randomization study.

We performed Mendelian randomization analyses of body mass index and waist-hip ratio adjusted for body mass index in Dupuytren's disease using summary statistics from genome-wide association study meta-analyses. We found that adiposity is causally protective against Dupuytren's disease, with the inverse-variance weighted Mendelian randomization analysis estimating that a 1 standard deviation increase in body mass index (equivalent to 4.8 kg/m2) leads to 28% (95% confidence interval: 18-37%) lower relative odds of developing Dupuytren's disease, and a 1 standard deviation increase in waist-hip ratio adjusted for body mass index (equivalent to a waist-hip ratio of 0.09) leads to 26% (95% confidence interval: 6-42%) lower relative odds of developing Dupuytren's disease. We conclude from this study that regardless of the well-established negative health effects of obesity, the raised body mass index is associated with a lower risk of Dupuytren's disease and may be causally protective for the development of the disease