Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple—even distinct—traits. ...Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10−8) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10−7) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes.
When many (up to millions) of statistical tests are conducted in discovery set analyses such as genome-wide association studies (GWAS), approaches controlling family-wise error rate (FWER) or false ...discovery rate (FDR) are required to reduce the number of false positive decisions. Some methods were specifically developed in the context of high-dimensional settings and partially rely on the estimation of the proportion of true null hypotheses. However, these approaches are also applied in low-dimensional settings such as replication set analyses that might be restricted to a small number of specific hypotheses. The aim of this study was to compare different approaches in low-dimensional settings using (a) real data from the CKDGen Consortium and (b) a simulation study.
In both application and simulation FWER approaches were less powerful compared to FDR control methods, whether a larger number of hypotheses were tested or not. Most powerful was the q-value method. However, the specificity of this method to maintain true null hypotheses was especially decreased when the number of tested hypotheses was small. In this low-dimensional situation, estimation of the proportion of true null hypotheses was biased.
The results highlight the importance of a sizeable data set for a reliable estimation of the proportion of true null hypotheses. Consequently, methods relying on this estimation should only be applied in high-dimensional settings. Furthermore, if the focus lies on testing of a small number of hypotheses such as in replication settings, FWER methods rather than FDR methods should be preferred to maintain high specificity.
African ancestry alleles may contribute to CKD among Hispanics/Latinos, but whether associations differ by Hispanic/Latino background remains unknown. We examined the association of CKD measures with ...African ancestry-specific
alleles that were directly genotyped and sickle cell trait (hemoglobin subunit
gene
variant) on the basis of imputation in 12,226 adult Hispanics/Latinos grouped according to Caribbean or Mainland background. We also performed an unbiased genome-wide association scan of urine albumin-to-creatinine ratios. Overall, 41.4% of participants were male, 44.6% of participants had a Caribbean background, and the mean age of all participants was 46.1 years. The Caribbean background group, compared with the Mainland background group, had a higher frequency of two
alleles (1.0% versus 0.1%) and the
variant (2.0% versus 0.7%). In the Caribbean background group, presence of
alleles (2 versus 0/1 copies) or the
variant (1 versus 0 copies) were significantly associated with albuminuria (odds ratio OR, 3.2; 95% confidence interval 95% CI, 1.7 to 6.1; and OR, 2.6; 95% CI, 1.8 to 3.8, respectively) and albuminuria and/or eGFR<60 ml/min per 1.73 m
(OR, 2.9; 95% CI, 1.5 to 5.4; and OR, 2.4; 95% CI, 1.7 to 3.5, respectively). The urine albumin-to-creatinine ratio genome-wide association scan identified associations with the
variant among all participants, with the strongest association in the Caribbean background group (
=3.1×10
versus
=9.3×10
for the Mainland background group). In conclusion, African-specific alleles associate with CKD in Hispanics/Latinos, but allele frequency varies by Hispanic/Latino background/ancestry.
Nonalcoholic fatty liver disease (NAFLD) disproportionally affects Hispanic/Latino populations. However, the magnitude varies among Hispanic/Latino ethnic groups. We investigated the mechanisms of ...these disparities.
We examined associations of NAFLD-associated genetic variants and continental ancestry with suspected NAFLD, levels of alanine aminotransferase (ALT), and liver fibrosis using data from the Hispanic Community Health Study/Study of Latinos-a population-based study of Hispanic/Latino adults in the United States. We evaluated data from 16,415 Hispanic/Latino adults in 4 cities from 2008 through 2011. Subjects suspected of having NAFLD or liver fibrosis were identified based on unexplained increases in levels of aminotransferases and FIB-4 score, respectively.
Among the 9342 participants with available genetic and aminotransferase data, the PNPLA3 G allele (odds ratio OR, 1.53; 95% CI, 1.41-1.66), TM6SF2 T allele (OR, 1.41; 95% CI, 1.20-1.67), and PPP1R3B G allele (OR, 1.16; 95% CI, 1.06-1.28) were associated with suspected NAFLD. PNPLA3 G was also associated with increased levels of ALT, except in participants with Dominican and South American backgrounds, and with liver fibrosis. The frequency of PNPLA3 G was high (41%) and TM6SF2 T (5%) was low in Hispanic/Latinos. PNPLA3 G frequency differed among Hispanic background groups with the highest proportion in Mexicans (52%) and the lowest proportion in Dominicans (23%). After adjustment for demographic, clinical, and behavioral factors, as well as PNPLA3 G, TM6SF2 T, and PPP1R3B G, American ancestry had a positive association with level of ALT (r = 6.61%; P < .001), whereas African (r = -3.84%; P < .001) and European (r = -4.31%; P < .001) ancestry were inversely associated with level of ALT.
American ancestry and PNPLA3 G are independent predictors of ALT levels in US Hispanic/Latinos and may in part explain NAFLD disparities in US Hispanic/Latinos.
Introduction
Non‐alcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic/Latinos and rates of NAFLD vary among Hispanics from different background groups. Genetic variants and ...continental ancestry contribute to NAFLD disparities among Hispanics. We evaluated two newly identified NAFLD‐associated single nucleotide polymorphisms of HSD17B13, rs72613567:TA and rs62305723:A in Hispanics/Latinos.
Methods
Clinical data, genotypes of variants of interest and estimates of continental ancestry were extracted from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) database, which includes a cohort of 16 415 US Hispanic/Latinos. Surrogate endpoints for NAFLD were suspected NAFLD based on unexplained aminotransferase elevation, continuous ALT levels and FIB‐4 scores to estimate hepatic fibrosis.
Results
In all, 9342 participants were included for analysis. The rs72613567:TA allele was found in 15.3% and the rs62305723:A allele was identified in 4.5% of HCHS/SOL participants. rs72613567:TA was less frequent in persons with vs without suspected NAFLD (12.4% vs 15.7%, P < .001) and rs72613567:TA was associated with lower FIB‐4 scores (P = .01). For persons with the NAFLD‐associated PNPLA3 rs738409:G allele, the presence of rs72613567:TA was associated with a lower rate of suspected NAFD (odds ratio = 0.76, P < .001). rs72613567:TA was less frequent in Hispanic/Latino background groups with higher rates of suspected NAFLD. The rs62305723:A allele was not associated with suspected NAFLD or FIB‐4 score.
Conclusion
The rs72613567:TA allele is associated with lower rates of suspected NAFLD and lower FIB‐4 scores among Hispanic/Latinos and with lower rates of suspected NAFLD in persons with the PNPLA3 rs738409:G allele. The rs72613567:TA allele contributes to NAFLD disparities among Hispanic/Latino background groups.
See Editorial on Page 756
Sickle cell disease (SCD) and apolipoprotein L1 (APOL1) G1/G2 variants increase chronic kidney disease (CKD) risk in African Americans by poorly understood mechanisms. We applied bioinformatics to ...identify new candidate genes associated with SCD‐related CKD. An interaction network demonstrated APOA1 connecting haemoglobin subunit β (HBB) and APOL1 with 36 other candidate genes. Gene expression revealed upregulation of engulfment and cell motility 1 (ELMO1) and downregulation of APOA1 in the kidney cortex of SCD versus non‐SCD mice. Analysis of candidate genes identified ELMO1 rs10951509 to be associated with albuminuria and APOA1 rs11216132 with haemoglobinuria in patients with SCD. A bioinformatic approach highlights ELMO1 and APOA1 as potentially associated with SCD nephropathy.
The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of ...population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex.
To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N = 326), African Americans (N = 324) and Hispanics (N = 327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within- and between-group heterogeneity.
As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.
High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several ...small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10−8) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
Background. Blood pressure (BP) control is poor among hypertensives in many parts of sub-Saharan Africa. A potentially modifiable factor for control of BP is medication nonadherence (MNA); our study ...therefore aimed to determine factors associated with MNA among hypertensives in Ghana and Nigeria. Methodology. We conducted a multicenter cross-sectional study. Patients were recruited from Korle-Bu Hospital (n=120), Ghana; and University of Port Harcourt Teaching Hospital, (n=73) Apapa General Hospital Lagos (n=79) and University College Hospital Ibadan (n=85), Nigeria. Results. 357 hypertensive patients (42.6% males) participated. MNA was found in 66.7%. Adherence showed correlation with depression (r=-0.208, P<0.001), concern about medications (r=-0.0347, P=0.002), and knowledge of hypertension (r=0.14, P=0.006). MNA was associated with formal education (P=0.001) and use of herbal preparation (P=0.014). MNA was found in 61.7% of uninsured participants versus 73.1% of insured participants (P=0.032). Poor BP control was observed in 69.7% and there was significant association between MNA and poor BP control (P=0.006). Conclusion. MNA is high among hypertensives in Ghana and Nigeria and is associated with depression, concern about hypertensive medications, formal education, and use of herbal preparations. The negative association between health insurance and MNA suggests interplay of other factors and needs further investigation.
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