Biology subjects

Wiberg, A.

Publications and source records attributed to Wiberg, A..

3 recordsLinked to original sources

bioRxiv2019

Genetic variants of calcium and vitamin D metabolism in kidney stone disease

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden1,2 with a heritability of ~45-60%3. To identify genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations, including 12,123 nephrolithiasis cases and 416,928 controls. Twenty loci associated with nephrolithiasis were identified, ten of which are novel. A novel CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of nephrolithiasis patients the CYP24A1-associated locus correlated with serum calcium concentration and number of kidney stone episodes, and the DGKD-associated locus correlated with urinary calcium excretion. Moreover, DGKD knockdown impaired CaSR-signal transduction in vitro, an effect that was rectifiable with the calcimimetic cinacalcet. Our findings indicate that genotyping may inform risk of incident kidney stone disease prior to vitamin D supplementation and facilitate precision-medicine approaches, by targeting CaSR-signaling or vitamin D activation pathways in patients with recurrent kidney stones.

genomics↗

bioRxiv2018

Characterization of the endocrine pancreas in Type 1 Diabetes: islet size is maintained but islet number is markedly reduced

Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of specific beta-cell loss. Since healthy pancreatic islets consist of ~65% beta cells, this would lead to reduced islet size if the beta cells are not replaced by other cells or tissue. The number of islets per pancreas volume (islet density) would not be affected.\n\nIn this study, we compared the islet density, size, and size distribution in subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. Results show that subjects with T1D, regardless of disease duration, had a dramatically reduced islet number per mm2, while the islet size was similar in all groups. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that frequently had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally expressed in beta cells.\n\nBased on our findings, we propose that failure during childhood to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.

pathology↗

bioRxiv2018

Human Handedness: Genetics, Microtubules, Neuropsychiatric Diseases and Brain Language Areas

BackgroundThe skew in distribution of handedness is a uniquely human trait, and has fascinated researchers for centuries. The heritability of handedness is estimated at 25%, but defining genetic variants contributing to this trait has so far proved elusive.\n\nMethodsWe performed GWAS of self-reported handedness in UK Biobank, a prospective cohort study of [~]500,000 individuals. Furthermore, we investigated correlations between our associated SNPs and brain imaging-derived phenotypes (IDPs) from >9,000 individuals in UK Biobank, as well as between self-reported handedness and IDPs.\n\nResultsOur association study of 38,322 left-handers vs 356,567 right-handers (excluding ambidextrous participants) revealed three genome-wide significant loci (rs199512, 17q21.31, p=4.1x10-9; rs45608532, 22q11.22, p=1.4x10-8; rs13017199, 2q34, p=3.3x10-8). In the imaging study, we found strong associations between rs199512 and diffusion MRI measures mainly in white matter tracts connecting language-related brain regions (p<2.0x10-6). Direct investigation between handedness and IDPs revealed numerous associations with functional connectivity between the same language-related areas of the brain. A second GWAS of non-right handers (n=44,631) vs right-handers (n=356,567) revealed an additional locus: rs3094128, 6p21.33, p=2.9x10-8. Three of the four associated loci (2q34, 17q21.31, 6p21.33) contain genes that encode microtubule-related proteins that are highly expressed in the brain: MAP2, MAPT and TUBB. These genes are strongly implicated in the pathogenesis of diseases that are known to affect an excess of left-handed people, including schizophrenia.\n\nConclusionsThis is the first GWAS to identify genome-wide significant loci for human handedness in the general population, and the genes at these loci have biological plausibility in contributing to neurodevelopmental lateralization of brain organisation, which appears to predispose both to left-handedness and to certain neurodegenerative and psychiatric diseases.

neuroscience↗