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...
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...
ABSTRACTMissing heritability in human diseases represents a major challenge. Although whole-genom... more ABSTRACTMissing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621...
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...
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...
ABSTRACTMissing heritability in human diseases represents a major challenge. Although whole-genom... more ABSTRACTMissing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621...
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