Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is... more Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth. Methods: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer. Results: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001). Conclusion: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted. M. Bauer et al.
The onset of bipolar disorder is influenced by the interaction of genetic and environmental facto... more The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduce...
The massive strides made in human genetics in the last 10 years would not have been possible with... more The massive strides made in human genetics in the last 10 years would not have been possible without the diligent and insightful work of the pioneers in human genetics. This is particularly true in South Africa (SA), where a small community of scientists and clinicians have been responsible for the application of scientific/ medical advances into the wider SA population. Prof. Peter Beighton spearheaded the initial retinal degenerative disorder (RDD) research project in 1985, the emphasis being the identification of genes underlying RDD in SA families. The RDD genes affect the rod and cone photoreceptors of the retina, resulting in retinal degeneration and consequent loss of vision, which may result in total blindness. At the time the project was initiated, it was believed there were, at most, three genes responsible for the most common RDD, namely retinitis pigmentosa (RP): one each for the autosomal dominant (ADRP), the autosomal recessive (ARRP) and the X-linked inherited (XLRP) forms. To date, however, there are 21, 34 and 2 genes for these forms of RP, respectively, [1] and over 230 genes for all forms of RDD worldwide. Generally, inherited RDDs are a challenging group of disorders to characterise, as they display vast clinical and genetic heterogeneity. Nevertheless, providing a genetic diagnosis to patients affords several benefits, including predictive, carrier and diagnostic testing for family members and participation in current and future gene-based clinical trials. Genetics in SA has its own unique challenges; the populations, both local and immigrant, exhibit genetic diversity of a higher order than other population groups. [2] Some groups have remained genetically isolated from each other, while others exhibit significant admixture. These phenomena have collectively contributed to unique, local variations in gene frequencies, noted in all SA population groups, which has further confounded genetic diagnosis for RDDs. Nevertheless, 'gene-hunting' for this group of disorders in SA has changed dramatically over the 25 years since the project began, largely through evolving molecular technologies, together with the computational era and increasing bioinformatics capabilities. This article gives an overview of the research efforts in SA into RDD.
Purpose:Two common approaches to identify subgroups of patients with bipolar disorder are cluster... more Purpose:Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.Methods:The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.Results:There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were fo...
ObjectiveTo confirm prior findings that the larger the maximum monthly increase in solar insolati... more ObjectiveTo confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.MethodData were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth‐cohort, family history, polarity of first episode and country physician density.ResultsThere was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth‐cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth‐cohort (all estimated coefficients P < 0.001).ConclusionA large increas...
Background Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than... more Background Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than 40 years, and hereditary factors may contribute. We investigated the frequency and patterns of inherited colorectal cancer among black Zimbabweans. Methods A population-based cross-sectional study of ninety individuals with a new diagnosis of colorectal cancer was carried out in Harare, Zimbabwe between November 2012 and December 2015. Phenotypic data was obtained using interviewer administered questionnaires, and reviewing clinical and pathology data. Cases were screened for mismatch repair deficiency by immunohistochemistry and/or microsatellite instability testing, and for MLH1, MSH2 and EPCAM deletions using multiplex ligation-dependent probe amplification. Next generation sequencing using a 16-gene panel was performed for cases with phenotypic features consistent with familial colorectal cancer. Variants were assessed for pathogenicity using the mean allele frequency, phenotypic features and searching online databases. Results Three Lynch syndrome cases were identified: MSH2 c.2634G>A pathogenic mutation, c. (1896+1_1897-1)_(*193_?)del , and one fulfilling the Amsterdam criteria, with MLH1 and PMS2 deficiency, but no identifiable pathogenic mutation. Two other cases had a strong family history of cancers, but the exact syndrome was not identified. The prevalence of
Consideration of molecular autopsies in forensic cases of sudden unexpected death in infants and ... more Consideration of molecular autopsies in forensic cases of sudden unexpected death in infants and children in South Africa This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.
The study of proteins and the interactions between them, known as Protein-Protein Interactions (P... more The study of proteins and the interactions between them, known as Protein-Protein Interactions (PPI), is extremely important in interpreting all biological cellular functions. In this article, a new web tool called Superclusteroid is presented which can analyse PPI data, in order to detect protein complexes or characterise the functionality of unknown proteins. The tool is essentially an intuitive PPI data processing pipeline. It supports various input file formats and provides services such as clustering, PPI network visualisation and protein cluster function prediction. Each Superclusteroid service can be used in a sequential manner or on an individual basis. In order to assess the reliability of our tool to infer PPIs, the results of the tool were compared to already known MIPS database complexes and a case scenario is presented where a known protein complex is predicted and the functionality of some of its proteins is revealed. Availability: Superclusteroid is freely available o...
SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in m... more SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We further find significantly higher language transmission rates for matrilineal groups as compa...
There is a glaring disparity in the populations included in genetic research; the majority of wor... more There is a glaring disparity in the populations included in genetic research; the majority of work involves European-derived cohorts, while other global populations - including Africans - are underrepresented. This is also true for the study of inherited retinal diseases. Being the most ancient of extant populations, African samples carry more variation than others, making them valuable for novel gene and variant discovery. The inclusion of diverse populations in research is essential to gain a more comprehensive understanding of genetic variation and molecular mechanisms of disease.
Importance Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent... more Importance Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD. Objective To identify common genetic loci associated with RHD susceptibility in Black African individuals. Design, Setting, and Participants This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021. Main Outcomes and Measures Genetic associations with RHD. Results This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10-8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10-3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10-5) in Black African individuals. Conclusions and Relevance This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.
Background Bipolar disorder is associated with circadian disruption and a high risk of suicidal b... more Background Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results This analysis confirmed the results of the exploratory study with the same best model and slightly...
BackgroundThe GRCh37 human genome assembly is still widely used in genomics despite the fact an u... more BackgroundThe GRCh37 human genome assembly is still widely used in genomics despite the fact an updated human genome assembly (GRCh38) has been available for many years. A particular issue with relevant ramifications for clinical genetics currently is the case of the GRCh37 Ensembl gene annotations which has been archived, and thus not updated, since 2013. These Ensembl GRCh37 gene annotations are just as ubiquitous as the former assembly and are the default gene models used and preferred by the majority of genomic projects internationally. In this study, we highlight the issue of genes with discrepant annotations, that have been recognized as protein coding in the new but not the old assembly. These genes are ignored by all genomic resources that still rely on the archived and outdated gene annotations. Moreover, the majority if not all of these discrepant genes (DGs) are automatically discarded and ignored by all variant prioritization tools that rely on the GRCh37 Ensembl gene an...
BackgroundGenetic studies of biomedical phenotypes in underrepresented populations identify dispr... more BackgroundGenetic studies of biomedical phenotypes in underrepresented populations identify disproportionate numbers of novel associations. However, current genomics infrastructure--including most genotyping arrays and sequenced reference panels--best serves populations of European descent. A critical step for facilitating genetic studies in underrepresented populations is to ensure that genetic technologies accurately capture variation in all populations. Here, we quantify the accuracy of low-coverage sequencing in diverse African populations.ResultsWe sequenced the whole genomes of 91 individuals to high-coverage (≥20X) from the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study, in which participants were recruited from Ethiopia, Kenya, South Africa, and Uganda. We empirically tested two data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those fro...
International Journal of Environmental Research and Public Health
Suicide rates worldwide are declining; however, less is known about the patterns and trends in mo... more Suicide rates worldwide are declining; however, less is known about the patterns and trends in mortality from suicide in sub-Saharan Africa. This study evaluates trends in suicide rates and years of potential life lost from death registration data in South Africa from 1997 to 2016. Suicide (X60–X84 and Y87) was coded using the 10th Revision of the International Classification of Diseases (ICD-10). Changes in mortality rate trends were analysed using joinpoint regression analysis. The 20-year study examines 8573 suicides in South Africa, comprising 0.1% of all deaths involving persons 15 years and older. Rates of suicide per 100,000 population were 2.07 in men and 0.49 in women. Joinpoint regression analyses showed that, while the overall mortality rate for male suicides remained stable, mortality rates due to hanging and poisoning increased by 3.9% and 3.5% per year, respectively. Female suicide mortality rates increased by 12.6% from 1997 to 2004 before stabilising; while rates due...
Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is... more Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth. Methods: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer. Results: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001). Conclusion: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted. M. Bauer et al.
The onset of bipolar disorder is influenced by the interaction of genetic and environmental facto... more The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduce...
The massive strides made in human genetics in the last 10 years would not have been possible with... more The massive strides made in human genetics in the last 10 years would not have been possible without the diligent and insightful work of the pioneers in human genetics. This is particularly true in South Africa (SA), where a small community of scientists and clinicians have been responsible for the application of scientific/ medical advances into the wider SA population. Prof. Peter Beighton spearheaded the initial retinal degenerative disorder (RDD) research project in 1985, the emphasis being the identification of genes underlying RDD in SA families. The RDD genes affect the rod and cone photoreceptors of the retina, resulting in retinal degeneration and consequent loss of vision, which may result in total blindness. At the time the project was initiated, it was believed there were, at most, three genes responsible for the most common RDD, namely retinitis pigmentosa (RP): one each for the autosomal dominant (ADRP), the autosomal recessive (ARRP) and the X-linked inherited (XLRP) forms. To date, however, there are 21, 34 and 2 genes for these forms of RP, respectively, [1] and over 230 genes for all forms of RDD worldwide. Generally, inherited RDDs are a challenging group of disorders to characterise, as they display vast clinical and genetic heterogeneity. Nevertheless, providing a genetic diagnosis to patients affords several benefits, including predictive, carrier and diagnostic testing for family members and participation in current and future gene-based clinical trials. Genetics in SA has its own unique challenges; the populations, both local and immigrant, exhibit genetic diversity of a higher order than other population groups. [2] Some groups have remained genetically isolated from each other, while others exhibit significant admixture. These phenomena have collectively contributed to unique, local variations in gene frequencies, noted in all SA population groups, which has further confounded genetic diagnosis for RDDs. Nevertheless, 'gene-hunting' for this group of disorders in SA has changed dramatically over the 25 years since the project began, largely through evolving molecular technologies, together with the computational era and increasing bioinformatics capabilities. This article gives an overview of the research efforts in SA into RDD.
Purpose:Two common approaches to identify subgroups of patients with bipolar disorder are cluster... more Purpose:Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.Methods:The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.Results:There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were fo...
ObjectiveTo confirm prior findings that the larger the maximum monthly increase in solar insolati... more ObjectiveTo confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.MethodData were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth‐cohort, family history, polarity of first episode and country physician density.ResultsThere was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth‐cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth‐cohort (all estimated coefficients P < 0.001).ConclusionA large increas...
Background Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than... more Background Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than 40 years, and hereditary factors may contribute. We investigated the frequency and patterns of inherited colorectal cancer among black Zimbabweans. Methods A population-based cross-sectional study of ninety individuals with a new diagnosis of colorectal cancer was carried out in Harare, Zimbabwe between November 2012 and December 2015. Phenotypic data was obtained using interviewer administered questionnaires, and reviewing clinical and pathology data. Cases were screened for mismatch repair deficiency by immunohistochemistry and/or microsatellite instability testing, and for MLH1, MSH2 and EPCAM deletions using multiplex ligation-dependent probe amplification. Next generation sequencing using a 16-gene panel was performed for cases with phenotypic features consistent with familial colorectal cancer. Variants were assessed for pathogenicity using the mean allele frequency, phenotypic features and searching online databases. Results Three Lynch syndrome cases were identified: MSH2 c.2634G>A pathogenic mutation, c. (1896+1_1897-1)_(*193_?)del , and one fulfilling the Amsterdam criteria, with MLH1 and PMS2 deficiency, but no identifiable pathogenic mutation. Two other cases had a strong family history of cancers, but the exact syndrome was not identified. The prevalence of
Consideration of molecular autopsies in forensic cases of sudden unexpected death in infants and ... more Consideration of molecular autopsies in forensic cases of sudden unexpected death in infants and children in South Africa This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.
The study of proteins and the interactions between them, known as Protein-Protein Interactions (P... more The study of proteins and the interactions between them, known as Protein-Protein Interactions (PPI), is extremely important in interpreting all biological cellular functions. In this article, a new web tool called Superclusteroid is presented which can analyse PPI data, in order to detect protein complexes or characterise the functionality of unknown proteins. The tool is essentially an intuitive PPI data processing pipeline. It supports various input file formats and provides services such as clustering, PPI network visualisation and protein cluster function prediction. Each Superclusteroid service can be used in a sequential manner or on an individual basis. In order to assess the reliability of our tool to infer PPIs, the results of the tool were compared to already known MIPS database complexes and a case scenario is presented where a known protein complex is predicted and the functionality of some of its proteins is revealed. Availability: Superclusteroid is freely available o...
SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in m... more SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We further find significantly higher language transmission rates for matrilineal groups as compa...
There is a glaring disparity in the populations included in genetic research; the majority of wor... more There is a glaring disparity in the populations included in genetic research; the majority of work involves European-derived cohorts, while other global populations - including Africans - are underrepresented. This is also true for the study of inherited retinal diseases. Being the most ancient of extant populations, African samples carry more variation than others, making them valuable for novel gene and variant discovery. The inclusion of diverse populations in research is essential to gain a more comprehensive understanding of genetic variation and molecular mechanisms of disease.
Importance Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent... more Importance Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD. Objective To identify common genetic loci associated with RHD susceptibility in Black African individuals. Design, Setting, and Participants This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021. Main Outcomes and Measures Genetic associations with RHD. Results This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10-8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10-3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10-5) in Black African individuals. Conclusions and Relevance This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.
Background Bipolar disorder is associated with circadian disruption and a high risk of suicidal b... more Background Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results This analysis confirmed the results of the exploratory study with the same best model and slightly...
BackgroundThe GRCh37 human genome assembly is still widely used in genomics despite the fact an u... more BackgroundThe GRCh37 human genome assembly is still widely used in genomics despite the fact an updated human genome assembly (GRCh38) has been available for many years. A particular issue with relevant ramifications for clinical genetics currently is the case of the GRCh37 Ensembl gene annotations which has been archived, and thus not updated, since 2013. These Ensembl GRCh37 gene annotations are just as ubiquitous as the former assembly and are the default gene models used and preferred by the majority of genomic projects internationally. In this study, we highlight the issue of genes with discrepant annotations, that have been recognized as protein coding in the new but not the old assembly. These genes are ignored by all genomic resources that still rely on the archived and outdated gene annotations. Moreover, the majority if not all of these discrepant genes (DGs) are automatically discarded and ignored by all variant prioritization tools that rely on the GRCh37 Ensembl gene an...
BackgroundGenetic studies of biomedical phenotypes in underrepresented populations identify dispr... more BackgroundGenetic studies of biomedical phenotypes in underrepresented populations identify disproportionate numbers of novel associations. However, current genomics infrastructure--including most genotyping arrays and sequenced reference panels--best serves populations of European descent. A critical step for facilitating genetic studies in underrepresented populations is to ensure that genetic technologies accurately capture variation in all populations. Here, we quantify the accuracy of low-coverage sequencing in diverse African populations.ResultsWe sequenced the whole genomes of 91 individuals to high-coverage (≥20X) from the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study, in which participants were recruited from Ethiopia, Kenya, South Africa, and Uganda. We empirically tested two data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those fro...
International Journal of Environmental Research and Public Health
Suicide rates worldwide are declining; however, less is known about the patterns and trends in mo... more Suicide rates worldwide are declining; however, less is known about the patterns and trends in mortality from suicide in sub-Saharan Africa. This study evaluates trends in suicide rates and years of potential life lost from death registration data in South Africa from 1997 to 2016. Suicide (X60–X84 and Y87) was coded using the 10th Revision of the International Classification of Diseases (ICD-10). Changes in mortality rate trends were analysed using joinpoint regression analysis. The 20-year study examines 8573 suicides in South Africa, comprising 0.1% of all deaths involving persons 15 years and older. Rates of suicide per 100,000 population were 2.07 in men and 0.49 in women. Joinpoint regression analyses showed that, while the overall mortality rate for male suicides remained stable, mortality rates due to hanging and poisoning increased by 3.9% and 3.5% per year, respectively. Female suicide mortality rates increased by 12.6% from 1997 to 2004 before stabilising; while rates due...
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Papers by Raj Ramesar