Genetic analysis localizes a novel locus on chromosome 4q for the glaucoma endophenotype, cup-to-disc ratio: The Jiri Eye Study

Purpose: Glaucoma is a heterogeneous disease influenced by genetic risk factors. However, not all genetic risk factors have been identified. The aim of this project is to localize genetic factors influencing known glaucoma endophenotypes: intraocular pressure (IOP), central corneal thickness (CCT), and vertical cup-to-disc ratio (VCDR). Methods: This family-based study design utilizes phenotypic and genomic data from a single well-characterized pedigree residing in the Jiri region of Nepal. Measures of IOP, CCT and VCDR were obtained by Goldmann applanation tonometry, OCT, and slit lamp biomicroscopy, respectively. Using a genome-wide genotype data set (~550,000 SNPs), we performed a genome-wide linkage scan for IOP, CCT, and VCDR adopting a quantitative approach in SOLAR. For localized quantitative trait locus (QTL) signals, we screened all SNPs within the 1-LOD (95% confidence) interval using the classical measured genotype approach to association analysis and allowing for non-independence amongst the pedigree members. Results: For this study, phenotypic and genotype data from 1,163 (55% female) members of the Jirel population were available. The mean age of the sample is 43.8 (SD=15.7) years. IOP (h2=19%, p=6.1×10-5), CCT (h2=57%, p=1.6×10-26), and VCDR (h2=48%, p=9.7×10-22) were significantly heritable. We localized a significant QTL for VCDR on chromosome 4 (LOD=3.05 at 86.83 Mb). The top association signal within this QTL was for an intronic SNP (rs4148155; p=2.01×10-6, b=0.24) in the ABCG2 (ATP binding cassette subfamily G member 2) gene, which satisfied our QTL-specific Bonferroni-corrected significance criterion (p\u3c6.59×10-5). ABCG2 is a known stem cell marker, which is positively expressed in clonal human trabecular meshwork stem cells. Another positional candidate gene of note is SCD5 (Stearoyl-CoA desaturase 5), which is shown to suppress neurite outgrowth, a marker of neuronal differentiation. SCD5 is of significant interest given that expression of myocilin (MYOC) also inhibits neurite outgrowth. Conclusions: To our knowledge, the VCDR QTL on chromosome 4 is a novel locus and does not overlap with other glaucoma endophenotypes or glaucoma disease status. These results highlight the importance of continued evaluation of genetic factors influencing glaucoma endophenotypes in under-studied populations, such as the Jirels, as new information may be elucidated

Landscape Genetics Reveals Focal Transmission of a Human Macroparasite

Macroparasite infections (e.g., helminths) remain a major human health concern. However, assessing transmission dynamics is problematic because the direct observation of macroparasite dispersal among hosts is not possible. We used a novel landscape genetics approach to examine transmission of the human roundworm Ascaris lumbricoides in a small human population in Jiri, Nepal. Unexpectedly, we found significant genetic structuring of parasites, indicating the presence of multiple transmission foci within a small sampling area (∼14 km2). We analyzed several epidemiological variables, and found that transmission is spatially autocorrelated around households and that transmission foci are stable over time despite extensive human movement. These results would not have been obtainable via a traditional epidemiological study based on worm counts alone. Our data refute the assumption that a single host population corresponds to a single parasite transmission unit, an assumption implicit in many classic models of macroparasite transmission. Newer models have shown that the metapopulation-like pattern observed in our data can adversely affect targeted control strategies aimed at community-wide impacts. Furthermore, the observed metapopulation structure and local mating patterns generate an excess of homozygotes that can accelerate the spread of recessive traits such as drug resistance. Our study illustrates how molecular analyses complement traditional epidemiological information in providing a better understanding of parasite transmission. Similar landscape genetic approaches in other macroparasite systems will be warranted if an accurate depiction of the transmission process is to be used to inform effective control strategies

Host genetics and population structure effects on parasitic disease

Host genetic factors exert significant influences on differential susceptibility to many infectious diseases. In addition, population structure of both host and parasite may influence disease distribution patterns. In this study, we assess the effects of population structure on infectious disease in two populations in which host genetic factors influencing susceptibility to parasitic disease have been extensively studied. The first population is the Jirel population of eastern Nepal that has been the subject of research on the determinants of differential susceptibility to soil-transmitted helminth infections. The second group is a Brazilian population residing in an area endemic for Trypanosoma cruzi infection that has been assessed for genetic influences on differential disease progression in Chagas disease. For measures of Ascaris worm burden, within-population host genetic effects are generally more important than host population structure factors in determining patterns of infectious disease. No significant influences of population structure on measures associated with progression of cardiac disease in individuals who were seropositive for T. cruzi infection were found

Canine Distemper Virus in Tigers (Panthera tigris) and Leopards (P. pardus) in Nepal

From wild dogs (Lycaon pictus) in the Serengeti to tigers (Panthera tigris altaica) in the Russian Far East, canine distemper virus (CDV) has been repeatedly identified as a threat to wild carnivores. Between 2020 and 2022, six Indian leopards (P. pardus fusca) presented to Nepali authorities with fatal neurological disease, consistent with CDV. Here, we report the findings of a serosurvey of wild felids from Nepal. A total of 48 serum samples were tested, comprising 28 Bengal tigers (P. t. tigris) and 20 Indian leopards. Neutralizing antibodies were identified in three tigers and six leopards, equating to seroprevalences of 11% (CI: 2.8–29.3%, n = 28) and 30% (CI: 12.8–54.3%, n = 20), respectively. More than one-third of seropositive animals were symptomatic, and three died within a week of being sampled. The predation of domestic dogs (Canis lupus familiaris) has been posited as a potential route of infection. A comparison of existing diet studies revealed that while leopards in Nepal frequently predate on dogs, tigers do not, potentially supporting this hypothesis. However, further work, including molecular analyses, would be needed to confirm this

Taking sociology seriously: a new approach to the bioethical problems of infectious disease

After a history of neglect, bioethicists have recently turned their attention to the topic of infectious disease. In this paper we link bioethicists' earlier neglect of infectious disease to their under-appreciation of the extent to which the problem of infectious disease is related to social factors and thus to questions of justice. We argue that a social causation of illness model - well-known to sociologists of medicine, but incompletely understood by bioethicists - will improve future bioethical analysis of issues related to infectious disease. By emphasising the relationships between social and economic structures of inequality and health, the social causation model provides a richer approach to ethical issues associated with infectious disease than the more commonly used biomedical model

Adult Children's Migration and Health-Related Quality of Life Among Older Nepali Adults

Traditionally, adult children have served as primary caretakers and providers for older Nepali adults. However, out-migration of adult children for employment and other opportunities is increasing. Health-related quality of life (HRQOL) in older Nepali adults in general and in the context of adult children's migration is poorly understood. This study aims to assess HRQOL of older Nepali adults and its relationship with adult children's migration. We used existing cross-sectional survey data on 260 older adults from Krishnapur municipality, which has witnessed a high rate of adult migration. HRQOL, quantified using the SF-12 scale, is expressed in terms of a physical (PCS) and mental (MCS) health component. A higher PCS and MCS score, each ranging from 0 to 100, indicates better physical and mental health, respectively. The correlates of HRQOL were assessed in simple and multiple linear regression. Participants had suboptimal HRQOL [mean (± SD): PCS = 40.4 ± 9.2 and MCS = 45.2 ± 7.7]. After adjusting for covariates, adult children's migration was associated with lower MCS scores (β: -2.33, 95%CI: -4.21, -0.44). Individuals with more than one child had higher MCS scores (β: 2.14, 95%CI: 0.19, 4.09). Females (β: -3.64, 95%CI: -7.21, -0.06) and those with a history of unemployment (β: -6.36, 95%CI: -10.57, -2.15) had lower PCS scores than their respective counterparts. The presence of chronic conditions was associated with significantly lower PCS and MCS scores. Our findings suggest that adult children's migration may negatively affect HRQOL among older Nepali adults, specifically their psychological well-being. Further research investigating potential moderating factors that may serve as important buffers is needed.</p

Quantitative physical activity assessment of children and adolescents in a rural population from Eastern Nepal

Objectives We report cross-sectional, objectively measured physical activity data for 399 children and adolescents aged 6 to 18 years. We evaluated physical activity of children and adolescents, considered time spent in each activity intensity category, and explored the impact of growth disruption (stunting and wasting) on physical activity patterns. Methods Participants wore an Actical (Mini-Mitter, Bend, OR) omnidirectional accelerometer for one week as part of their annual visit to the Jiri Growth Study. The percentage of time spent in standard activity intensities were computed using standard metabolic equivalents (METS) cutpoints and compared by chronological age, sex, and school versus non-school days. Results Primary findings include (1) children are more active on non-school days and adolescents are more active during the school week; (2) Jirel children do not exhibit the reduction in physical activity that most Western populations experience during the transition from childhood to adolescence; and (3) Jirel children and adolescents routinely meet the suggested one hour/day MVPA threshold; (4) Stunting is prevalent and factors leading to this growth disruption may contribute to the amount of time in sedentary or light physical activity. Conclusions We report child and adolescent physical activity patterns from the Jirel population of eastern Nepal. In this rural context, children and adolescents are more active than populations reported from Western contexts. This key finding has important biomedical implications for the maintenance of healthy body composition, skeletal health, and other health traits. Am. J. Hum. Biol. 28:129–137, 2016

Perceptions towards COVID-19 Vaccines and Willingness to Vaccinate in Nepal

Vaccination is the most effective preventive measure of COVID-19 available at present, but its success depends on the global accessibility of vaccines and the willingness of people to be vaccinated. As the vaccination rollouts are increasing worldwide, it is important to assess public perception and willingness towards vaccination, so that the aim of mass vaccination will be successful. This study aimed to understand public perception towards COVID-19 vaccines and their willingness to get vaccinated in Nepal. This cross-sectional online survey was conducted among 1196 residents of Nepal in August 2021; most of the participants of this online survey were young adults (18&ndash;47 years) with university-level education. A total of 64.5% (771/1196) of the participants perceived COVID-19 vaccines to be safe and risk-free, while 68.6% (820/1196) agreed that vaccination would be efficient in the fight against this pandemic. Most of the participants (841/1196, 70.3%) disagreed that people are getting COVID-19 vaccines easily in Nepal, while they agree with the prioritization of older adults and healthcare workers for vaccination. A total of 61.1% (731/1196) of the participants had received at least one dose of the vaccine. Among the unvaccinated, 93.3% (434/465) were willing to get vaccinated when their turn came. The higher confidence of younger adults in vaccines and the vaccination process is encouraging, as that can help educate others who are hesitant or are not positive towards the idea of receiving vaccines. Dissemination of correct and current information, acquisition of enough doses of vaccines, and equitable distribution of vaccines will be required to achieve successful completion of the COVID-19 vaccination campaign in Nepal

Genetic influences on dentognathic morphology in the Jirel population of Nepal

Patterns of genetic variation and covariation impact the evolution of the craniofacial complex and contribute to clinically significant malocclusions in modern human populations. Previous quantitative genetic studies have estimated the heritabilities and genetic correlations of skeletal and dental traits in humans and nonhuman primates, but none have estimated these quantitative genetic parameters across the dentognathic complex. A large and powerful pedigree from the Jirel population of Nepal was leveraged to estimate heritabilities and genetic correlations in 62 maxillary and mandibular arch dimensions, incisor and canine lengths, and post-canine tooth crown areas (N ≥ 739). Quantitative genetic parameter estimation was performed using maximum likelihood-based variance decomposition. Residual heritability estimates were significant for all traits, ranging from 0.269 to 0.898. Genetic correlations were positive for all trait pairs. Principal components analyses of the phenotypic and genetic correlation matrices indicate an overall size effect across all measurements on the first principal component. Additional principal components demonstrate positive relationships between post-canine tooth crown areas and arch lengths and negative relationships between post-canine tooth crown areas and arch widths, and between arch lengths and arch widths. Based on these findings, morphological variation in the human dentognathic complex may be constrained by genetic relationships between dental dimensions and arch lengths, with weaker genetic correlations between these traits and arch widths allowing for variation in arch shape. The patterns identified are expected to have impacted the evolution of the dentognathic complex and its genetic architecture as well as the prevalence of dental crowding in modern human populations