Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men.

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Testing the generalizability of ancestry-specific polygenic risk scores to predict prostate cancer in sub-Saharan Africa.

BACKGROUND: Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa. RESULTS: Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608-0.707, OR 2.37-5.71) than for African individuals (AUC 0.502-0.585, OR 0.95-2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores. CONCLUSIONS: Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.

Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: A meta-analysis within diverse populations.

Background: We recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program and additional independent studies. Methods: Within each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case-control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population. Results: The PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8794 cases, 55,657 controls), and Hispanic (1082 cases, 20,601 controls) populations. Comparing men in the top decile (90-100% of the PRS) to the average 40-60% PRS category, the prostate cancer odds ratio (OR) was 3.8-fold in European ancestry men (95% CI = 3.62-3.96), 2.8-fold in African ancestry men (95% CI = 2.59-3.03), and 3.2-fold in Hispanic men (95% CI = 2.64-3.92). The PRS did not discriminate risk of aggressive versus nonaggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: ≤55 years, OR = 7.11; 55-60 years, OR = 4.26; >70 years, OR = 2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk ~10 years younger than men in the 40-60% PRS category. Conclusions: Our findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine whether the PRS could be used for risk-stratified screening and early detection. Funding: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Determination of Serum Prostate Specific Antigen Levels Amongst Apparently Healthy Nigerian Males in a University and University Hospital Community in the Federal Capital Territory.

BACKGROUND: Prostate cancer is the commonest cancer among men worldwide and serum prostate specific antigen (PSA) has remained the most commonly applied screening test for the disease till date. Current PSA test results guidelines in our population are informed by reference intervals derived from studies from Caucasians and other racial groups. With scanty data on PSA reference values from our local population, this study evaluated the serum PSA levels of apparently healthy Nigerian male subjects in whom prostate cancer and urinary tract infection have been excluded. METHOD: This study had participants aged 40 to 70 years, with no lower urinary tract symptoms or other symptoms suggestive of prostate disease recruited from the male staff population of the University of Abuja and University of Abuja Teaching Hospital and the adjoining local community. They were physically examined, had prostate ultrasonography, urine analysis, and blood sample collected for PSA testing. Data collected was analyzed using Statistical Package for Social Science (SPSS) version 24. RESULT: Of a total of 210 men who participated in the study, 191 eventually met the inclusion criteria. The average age was 52.9 years, ninety seven percent of them had heard of prostate cancer before now. The mean total PSA was 1.46 ng/mL (SD +/-1.55), while the reference interval was .23-5.60 ng/mL. The average prostate size was 41.8 mL (SD+/-20.11), and there was a positive correlation between the PSA and the prostate size (.418) as well as the age of the subjects (.446). There was no significant difference in the mean PSA value for those with or without family history of prostate cancer (P=.979). CONCLUSION: The reference range of PSA in Nigeria is higher than in other races, hence utilizing a local value in decision making would help to reduce unnecessary invasive procedures.

Overall and central obesity and prostate cancer risk in African men.

PURPOSE: African men are disproportionately affected by prostate cancer (PCa). Given the increasing prevalence of obesity in Africa, and its association with aggressive PCa in other populations, we examined the relationship of overall and central obesity with risks of total and aggressive PCa among African men. METHODS: Between 2016 and 2020, we recruited 2,200 PCa cases and 1,985 age-matched controls into a multi-center, hospital-based case-control study in Senegal, Ghana, Nigeria, and South Africa. Participants completed an epidemiologic questionnaire, and anthropometric factors were measured at clinic visit. Multivariable logistic regression was used to examine associations of overall and central obesity with PCa risk, measured by body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), respectively. RESULTS: Among controls 16.4% were obese (BMI ≥ 30 kg/m2), 26% and 90% had WC > 97 cm and WHR > 0.9, respectively. Cases with aggressive PCa had lower BMI/obesity in comparison to both controls and cases with less aggressive PCa, suggesting weight loss related to cancer. Overall obesity (odds ratio: OR = 1.38, 95% CI 0.99-1.93), and central obesity (WC > 97 cm: OR = 1.60, 95% CI 1.10-2.33; and WHtR > 0.59: OR = 1.68, 95% CI 1.24-2.29) were positively associated with D'Amico intermediate-risk PCa, but not with risks of total or high-risk PCa. Associations were more pronounced in West versus South Africa, but these differences were not statistically significant. DISCUSSION: The high prevalence of overall and central obesity in African men and their association with intermediate-risk PCa represent an emerging public health concern in Africa. Large cohort studies are needed to better clarify the role of obesity and PCa in various African populations.

A Custom Genotyping Array Reveals Population-Level Heterogeneity for the Genetic Risks of Prostate Cancer and Other Cancers in Africa.

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array. SIGNIFICANCE: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.

Cavernosal artery peak systolic velocity among normal adults in Abuja, Nigeria: A Baseline parameter for sonographic diagnosis of vasculogenic erectile dysfunction

Background: Erectile dysfunction is consistent inability to achieve and maintain erection of sufficient rigidity for satisfactory sexual performance. It is well known that the hemodynamic function of the penis correlates well with the peak systolic velocity (PSV) of the cavernosal artery (CA) which is the most reliable, sensitive, and objective parameter used in evaluating the state of the erectile tissues of the penis. This study was aimed at establishing the normal CA PSV in this environment, as it may differ from the values among Americans, Caucasians, and Asians. Materials and Methods: The study was conducted between July 2015 and January 2017, at the Department of Radiology, Federal Medical Centre, Abuja. Twenty-nine consecutive patients referred by the urologist to the radiology department of the aforementioned institution for penile ultrasound were evaluated using triplex Doppler sonography with high-frequency linear array transducer. The penile scan was done before and after intracavernosal injection of 10­20 µg prostaglandin E1. The waveforms of CAs were obtained alternately using the angle of inclination ≤60°, and the PSV of the CA was documented at 5-min interval, from 5 to 40 min. Results: PSV of CA varied between 26 and 104.4 cm/s (mean: 46.72 ± 16.21) among the entire research participants. No significant discrepancy was noted between PSV of the right and left cavernosal arteries. The PSV had a strong positive relationship with age (P = 0.002), with the highest values found among those ≤30 years. Conclusion: The mean PSV of cavernosal arteries established in this study is not significantly different from the values obtained among Americans, Caucasians, and Asians, indicating that racial difference has no effect on this important sonographic variable

Male circumcision and HIV prevention.

INTRODUCTION: Growing evidence has linked circumcision with some protection against HIV infection. Should nations with a high HIV infection rate encourage male circumcision? METHODS: Four people with expertise and/or interest in the area of circumcision and HIV were asked to contribute their opinions. MAIN OUTCOME MEASURE: To provide food for thought, discussion, and possible further research in a poorly discussed area of sexual medicine. RESULTS: Three clinical trials in Africa showed the benefit of circumcision in reducing HIV incidence in men. Sadeghi-Nejad cites these, but balances this with the pandemic in India, and the cultural implications of circumcision. Pollack cites these studies as well, but reinforces the World Health Organization and UNAIDS recommendations that male circumcision should not replace safe sex. As a Nigerian, Aisuodionoe-Shadrach discusses the indirect ways in which circumcision can reduce the spread of HIV, and advocates the surgery, although he proposes infant circumcision may be wiser. Ira Sharlip, President of the International Society for Sexual Medicine, explains some of the physiology involved while again citing the three recent African studies. He questions who would be circumcised and who would perform the procedure if pro-circumcision policies were adopted. CONCLUSION: While three clinical trials in Africa were halted after it became evident that circumcision was beneficial in protecting against HIV, further information on the health risks and benefits of male circumcision is needed. Ethical decisions need to be made and medical recommendations developed before circumcision can be considered for HIV prevention.

Urethral duplication with a perineal opening in a four-year-old boy.

Urethral duplication (UD) is a rare congenital anomaly. In UD, there is in addition to a normally positioned urethra an accessory urethra arising from the bladder, bladder neck or the proximal urethra and terminating anywhere between the base of the penis along the ventral surface and the glans penis. The embryologic development of UD remains to be clearly elucidated and the etiology of the condition is unknown. We present our experience with a 4 year old boy who presented with urethral duplication.

Congenital complex penile curvature.

Congenital complex penile curvature is a rare deformity that arises from asymmetry of the corpora cavernosa. The deformity is generally not severe enough to interfere with sexual intercourse but can be a source of great concern to the patient and may cause him to avoid sexual contact altogether. We report a case of congenital complex penile curvature in a 21-year-old man who was satisfactorily corrected using the modified Nesbit procedure.