Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Funder: The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute he California Tobacco Related Research Program (3RT-0122; and; 10RT-0251) Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096CAbstract: Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

Sex differences in age‐related bone loss and antemortem tooth loss in East‐Central Arizona (AD 1200–1450)

Previous archaeological research on dental health in the New World has documented significant sex differences in antemortem tooth loss (AMTL), with a much higher rate of AMTL in females versus males, particularly during the transition to agriculture. While AMTL can be caused by multiple factors, including periodontal disease, attrition, trauma and cultural influences, sex differences are often attributed to the impact of female reproductive biology on oral health. Clinical research on osteoporosis has documented a significant relationship between AMTL and age-related bone loss, which disproportionately affects women. However, this relationship has not been systematically investigated in prehistoric populations. This study aims to address this issue by investigating the relationship between sex, AMTL and age-related bone loss in an archaeological sample from East-Central Arizona. AMTL, dental caries and radial and femoral cortical and trabecular bone mineral density (BMD) were measured in individuals from Point of Pines Pueblo, Arizona (AD 1200–1450). Our results revealed that while there was no statistically significant difference in AMTL between males and females in this sample, there were notable sex differences in the relationship between AMTL, caries, age and BMD. There was a significant association between caries, age and AMTL in females, but not in males. Conversely, while age had a significant effect on caries in males, there was no corresponding relationship in females. Cortical BMD had a moderate effect on AMTL in females, comparable to the effect of age, although this did not reach statistical significance. There was no significant effect of BMD on AMTL in males. The results suggest that biocultural processes differentially affected oral health in males and females at Point of Pines Pueblo, and that age-related cortical bone loss potentially impacted AMTL in females in this population, but further research is needed. © 2021 John Wiley & Sons, Ltd.University of Arizona12 month embargo; first published: 29 March 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Social isolation through single housing negatively affects trabecular and cortical bone in adult male, but not female, C57BL/6J mice

Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and loneliness, researchers have been concerned about a rising epidemic of loneliness. Isolation is associated with an increased risk for many physical and mental health disorders and increased overall mortality risk. In addition to social isolation, older adults are also at greater risk for osteoporosis and related fractures. While researchers have investigated the negative effects of other forms of psychosocial stress on bone, including depression and PTSD, the effects of social isolation on bone have not been thoroughly investigated. The aim of this study was to test the hypothesis that social isolation would lead to bone loss in male and female C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) for four weeks. Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI, Ct.Por.) parameters in male, but not female mice. Isolated male mice had signs of reduced bone remodeling represented by reduced osteoblast numbers, osteoblast-related gene expression and osteoclast-related gene expression. However, isolated females had increased bone resorption-related gene expression, without any change in bone mass. Overall, our data suggest that social isolation has negative effects on bone in male, but not female mice, although females showed suggestive effects on bone resorption. These results provide critical insight into the effects of isolation on bone and have key clinical implications as we grapple with the long-term health impacts of the rise in social isolation related to the COVID-19 pandemic

Thermoneutral housing does not rescue olanzapine-induced trabecular bone loss in C57BL/6J female mice

Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28-30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (-13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone

Thermoneutral housing does not rescue olanzapine-induced trabecular bone loss in C57BL/6J female mice

Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28–30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (−13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone

Association between measures derived from children's primary exfoliated teeth and psychopathology symptoms: Results from a community-based study

Mental disorders are among the most disabling health conditions globally. However, there remains a lack of valid, reliable, noninvasive, and inexpensive biomarkers to identify (at an early age) people who are at the greatest risk of experiencing a future mental health condition. Exfoliated primary teeth, when used in combination with established and emerging tools (e.g., family history, imaging, genetics, epigenetics), may provide important additional insights about vulnerability to mental illness. Teeth are especially promising because they develop in parallel with the brain and maintain a permanent record of environmental insults occurring during prenatal and perinatal development. Despite their potential, few empirical studies have investigated features of exfoliated teeth in relation to mental health. Here, we used micro-CT imaging to test the hypothesis that measures derived from exfoliated primary incisors associated with psychopathology symptoms in a community-based sample of children (N=37). We found that enamel volume (beta=-0.77, 95% CI, -1.35 to -0.18, P=.01) had large negative associations with internalizing symptoms and enamel mineral density (beta=0.77, 95% CI, 0.18 to 1.35, P=.01) had large positive associations with internalizing behavioral symptoms, even after stringent control for multiple testing. Pulp volume (beta=-0.50, 95% CI, -0.90 to -0.09, P=.02) had a moderately-large negative association with externalizing behavioral symptoms, though these associations did not survive multiple testing. These results support the ongoing investigation of teeth as potential novel biomarkers of mental health risk

Author Correction: Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

An amendment to this paper has been published and can be accessed via a link at the top of the paper

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.</p