Biology subjects

Walsh, J. P.

Publications and source records attributed to Walsh, J. P..

3 recordsLinked to original sources

bioRxiv2020

Genome-wide analyses point to differences in genetic architecture of BMI between tall and short people

To examine differences in the genetic architecture of BMI between tall and short people, we conducted genome-wide and follow-up analyses using UK Biobank data. We identify 57 loci as height-specific, detect differences in SNP-based heritability between tall and short people and show how genetic correlations between the two rises during the lifespan. Using phenome-wide analyses (PHEWAS), a significant association between a short people-specific locus on MC4R and energy portion size was detected. We identify one locus (GPC5-GPC6) with different effect directions on BMI in short and tall people. PHEWAS indicates this locus is associated with bone mineral density. Transcriptome-wide analyses hint that genes differentially associated with BMI in short vs tall people are enriched in brain tissue. Our findings highlight the role of height in the genetic underpinnings of BMI, provide biological insight into mechanisms underlying height-dependent differences in BMI and show that in short and tall people obesity is a risk factor that differentially increases susceptibility for disease.

genetics↗

bioRxiv2019

Multi-omic analyses reveal antibody-dependent natural killer cell-mediated cytotoxicity in autoimmune thyroid diseases

The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood. We previously observed systemic depletion of IgG core fucosylation and antennary 1,2 fucosylation of peripheral blood mononuclear cells in AITD, correlated with thyroid peroxidase antibody (TPOAb) levels. We hypothesized that deficiency in IgG core fucose enhances antibody-dependent cell-mediated cytotoxicity of thyrocytes by TPOAb, contributing to thyroid autoimmunity. Multi-omic evaluations in 622 individuals (172 with AITD) from the TwinsUK cohort showed decreased IgG core fucosylation levels associated with a subpopulation of natural killer (NK) cells featuring CD335, CD314, and CD158b immunoreceptors, and increased levels of apoptosis-associated Caspase-2 and Interleukin-1, positively associated with AITD. AITD-associated genetic variants rs1521 and rs3094228 alter expression of thyrocyte ligands of the CD314 and CD158b immunoreceptors on NK cells. The combination of low-core fucose IgG associated with an NK cell subpopulation and genetic variant-promoted ligand activation in thyrocytes may promote antibody-dependent NK cell-mediated cytotoxicity of thyrocytes in AITD.

immunology↗

bioRxiv2018

Decreased IgG core fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins (Igs) and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells (PBMCs) glycosylation with AITD and the influence of genetic background. The study revealed an inverse association of IgG core fucosylation with TPOAb and PBMCs antennary 1,2 fucosylation with AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity (ADCC) associated with TPOAb levels.

immunology↗