Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among ...study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
With increasing representation of global populations in genetic studies, there is an opportunity for advanced methods development and a need for consensus “best practices” for analyzing datasets. We provide background on the scientific and ethical importance of including underrepresented groups in genetics research and offer guidance for genome-wide analysis of ancestrally diverse study cohorts.
Sub-Saharan Africa has generally experienced few cases and deaths of coronavirus disease 2019 (COVID-19). In addition to other potential explanations for the few cases and deaths of COVID-19 such as ...the population socio-demographics, early lockdown measures and the possibility of under reporting, we hypothesize in this mini review that individuals with a recent history of malaria infection may be protected against infection or severe form of COVID-19. Given that both the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and
(
) merozoites bind to the cluster of differentiation 147 (CD147) immunoglobulin, we hypothesize that the immunological memory against
merozoites primes SARS-CoV-2 infected cells for early phagocytosis, hence protecting individuals with a recent
infection against COVID-19 infection or severity. This mini review therefore discusses the potential biological link between
infection and COVID-19 infection or severity and further highlights the importance of CD147 immunoglobulin as an entry point for both SARS-CoV-2 and
into host cells.
African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of ...genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.
Majara et al. show that polygenic scores generalize variably across diverse populations due to genetic differences between target and discovery cohorts. Multi-ancestry discovery GWAS typically improve prediction accuracy in underrepresented populations more than an increase in the European sample size, but not necessarily when sample sizes are imbalanced.
: Internalizing mental disorders (IMDs) among HIV-positive (HIV+) children and adolescents are associated with poor disease outcomes, such as faster HIV disease progression. Although it has been ...suggested that the development of IMDs is moderated by interaction of stressful life events and vulnerability factors, the underlying etiology is largely unknown. Serotonin transporter gene solute carrier family 6 member A4 (
) and human tryptophan hydroxylase 2 gene (
) polymorphisms have been implicated in the development of IMDs. This study investigated the association between acute stress and IMDs, and moderation by chronic stress and genetic variants in
and
.
: Acute stress acts through genetic and environmental vulnerability factors to increase the risk of developing IMDs.
: Polymorphisms in
(
, rs25531,
-rs25531, and
VNTR) and
(rs1843809, rs1386494, rs4570625, and rs34517220) were genotyped in 368 HIV+ children and adolescents (aged 5-17 years) with any internalizing mental disorder (depression, anxiety disorders, or posttraumatic stress disorder), and 368 age- and sex-matched controls, who were also HIV+. Chronic and acute stress categories were derived by hierarchical cluster analysis. Logistic regression analysis was used to assess the independent moderating effect of chronic stress and each selected polymorphism on the association between acute stress and IMDs.
: We observed a statistically significant association between severe acute stress and IMDs (
= 0.001). Children and adolescents who experienced severe acute stress were twice as likely to develop IMDs, compared to children and adolescents who experienced mild acute stress (
= 0.001). Chronic stress interacted with severe acute stress to increase the risk of IMDs (
= 0.033). Acute stress was found to interact with
-rs25531
haplotype to increase the risk for IMDs among Ugandan HIV+ children and adolescents (
= 0.049). We found no evidence for a combined interaction of acute stress, chronic stress, and
-rs25531 on IMDs.
: The odds of having an internalizing mental disorder (IMD) were higher among HIV+ children and adolescents who experienced severe acute stress compared to HIV+ children and adolescents who experienced mild acute stress. Chronic stress and
-rs25531 independently moderated the association between acute stress and IMDs.
Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not ...been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years).
We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months.
TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.
This study established the prevalence of physical and sexual victimization, associated factors and psychosocial consequences of victimization among 1,201 out-patients with severe mental illness at ...Butabika and Masaka hospitals in Uganda.
Participants completed structured, standardized and locally translated instruments. Physical and sexual victimization was assessed using the modified adverse life events module of the European Para-suicide Interview Schedule. We used logistic regression to determine the association between victimization, the associated factors and psychosocial consequences.
The prevalence of physical abuse was 34.1% and that of sexual victimization was 21.9%. The age group of > = 50 years (aOR 1.02;95% CI 0.62-1.66;
= 0.048) was more likely to have suffered physical victimization, while living in a rural area was protective against physical (aOR 0.59; 95% CI 0.46-0.76;
= <0.001) and sexual (aOR 0.48, 95% CI 0.35-0.65;
< 0.001) victimization. High socioeconomic status (SES) (aOR 0.56; 95% CI 0.34-0.92;
= <0.001) was protective against physical victimization. Females were more likely to have been sexually victimized (aOR 3.38; 95% CI 2.47-4.64;
= <0.001), while being a Muslim (aOR 0.60; 95% CI 0.39-0.90;
= 0.045) was protective against sexual victimization. Risky sexual behavior was a negative outcome associated with physical (aOR 2.19; 95% CI 1.66-2.90;
= <0.001) and sexual (aOR 3.09; 95% CI 2.25-4.23;
< 0.001) victimization. Mental health stigma was a negative outcome associated with physical (aOR 1.03; 95% CI 1.01-1.05;
< 0.001) and sexual (aOR 1.03; 95% CI 1.01-1.05;
= 0.002) victimization. Poor adherence to oral anti-psychotic medications was a negative outcome associated with physical (aOR 1.51; 95% CI 1.13-2.00;
= 0.006) and sexual (aOR 1.39; 95% CI 0.99-1.94;
= 0.044) victimization.
There is a high burden of physical and sexual victimization among people with SMI in central Uganda. There is need to put in place and evaluate complex interventions for improving detection and response to abusive experiences within mental health services. Public health practitioners, policymakers, and legislators should act to protect the health and rights of people with SMI in resource poor settings.
Children and adolescents living with human immunodeficiency virus (CA-HIV) suffer a considerable burden of internalizing disorders (IDs; depressive and anxiety disorders). Environmental and genetic ...factors have been reported to influence the vulnerability to IDs in western settings; however, their role among African populations remains inadequately explored. We investigated the individual and interactive effects of stress and single-nucleotide polymorphisms within the FK506 binding protein 5 (rs1360780) and glucocorticoid receptor (rs10482605) genes on ID status in a cohort of CA-HIV in Uganda. We genotyped rs10482605 (309 cases and 315 controls) and rs1360780 (350 cases and 335 controls) among CA-HIV with and without IDs using Kompetitive Allele-Specific PCR. Socio-demographic variables, as well as allele and genotype distributions, were compared between cases and controls using chi-square tests. Genotypes were assessed for Hardy-Weinberg equilibrium. Composite indices of recent and chronic stress classes were also generated. A hierarchical cluster analysis was used to generate cutoff points within each of the indices of recent and chronic stress. Logistic regression was used to assess the association between IDs and each of recent stress, chronic stress, and the investigated genotypes. The interaction effect of chronic/recent stress on the association between each of the polymorphisms and IDs was determined using a likelihood ratio test. We observed no significant association between IDs and rs1360780 and rs10482605 polymorphisms within the FKBP5 and glucocorticoid receptor genes, respectively (
> 0.050). Severe recent stress increased the vulnerability to IDs among CA-HIV (
= 0.001). We did not observe any gene-environment effect on vulnerability to IDs in this population. These findings support the currently held opinion that polymorphisms at single genetic loci only contribute a very small effect to the genetic vulnerability to IDs.
Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of ...cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated.
We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY).
IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe).
-tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex.
We observed longer rTL among cases of IMDs compared with controls (
< 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (
< 0.001). The same statistical difference was observed when cases and controls were individually analyzed (
< 0.001). We found no significant difference in rTL between cases and controls at 12 months (
= 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months.
rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings.
While psychiatric and physical comorbidities in severe mental illness (SMI) have been associated with increased mortality and poor clinical outcomes, problem has received little attention in low- and ...middle-income countries (LMICs). This study established the prevalence of psychiatric (schizophrenia, bipolar affective disorder, and recurrent major depressive disorder) and physical (HIV/AIDS, syphilis, hypertension and obesity) comorbidities and associated factors among 1201 out-patients with SMI (schizophrenia, depression and bipolar affective disorder) attending care at two hospitals in Uganda. Participants completed an assessment battery including structured, standardised and locally translated instruments. SMIs were established using the MINI International Neuropsychiatric Interview version 7.2. We used logistic regression to determine the association between physical and psychiatric comorbidities and potential risk factors. Bipolar affective disorder was the most prevalent (66.4%) psychiatric diagnoses followed by schizophrenia (26.6%) and recurrent major depressive disorder (7.0%). Prevalence of psychiatric comorbidity was 9.1%, while physical disorder comorbidity was 42.6%. Specific comorbid physical disorders were hypertension (27.1%), obesity (13.8%), HIV/AIDS (8.2%) and syphilis (4.8%). Potentially modifiable factors independently significantly associated with psychiatric and physical comorbidities were: use of alcohol for both syphilis and hypertension comorbidities; and use of a mood stabilisers and khat in comorbidity with obesity. Only psychiatric comorbidity was positively associated with the negative outcomes of suicidality and risky sexual behaviour. The healthcare models for psychiatric care in LMICs such as Uganda should be optimised to address the high burden of psychiatric and physical comorbidities.
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