Genome-wide Significant Signals Research Articles

#795 Genetics of serum electrolytes: a genome-wide association approach in two European cohorts

Abstract Background and Aims Chloride, potassium and sodium are electrolytes that play a key role in several physiological processes. To date, the genetic factors underlying their differences in the general population are not fully understood and need to be further investigated. In this study, we aimed at dissecting the genetics of the levels of these serum electrolytes in the European population by genomic approaches. Method We genotyped and analysed data from 3057 North-Eastern Italian individuals participating in the INCIPE (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points) cohort. Genomic data were processed for quality controls (using plink and bcftools), following these exclusion criteria: sample missingness >0.15, genotype missingness >0.02, relatedness up to 2nd degree, non-European ethnicity. Next, the dataset underwent genotype imputation on the Michigan Imputation Server, using the Human Reference Consortium panel and filtering for imputation confidence (R2 >0.3). Typed and imputed data were then analysed on genome-wide association studies (GWAS, using rvtest) for each of the three serum electrolytes. The same analytical procedure was applied to 14926 individuals from the Rotterdam Study (RS) cohort (a prospective cohort study ongoing since 1990 in Rotterdam). Thus, summary statistics from all the phenotypes and cohorts were jointly analysed in a genome-wide meta-analysis setting (using METAL). Meta-analyses results underwent functional annotation on the FUMAGWAS platform, to obtain biological and functional insights and to allow variants and genes prioritisation. Results Quality controls and genotype imputation resulted in a total of 857 (INCIPE1) and 1343 (INCIPE2) samples and 8 million variants for the INCIPE cohort; 2056 (RS1), 2042 (RS2) and 2958 (RS3) samples and 7.7 million variants for the Rotterdam Study cohort. GWAS showed genome-wide signals (p < 5e-8) for chloride and sodium and suggestive signals (p < 5e-5) for potassium. Meta-analyses partially replicated results obtained on the INCIPE cohort, showing signals for all the three electrolytes over the suggestive threshold only. Finally, functional annotation gave insights on associated genes and markers. Chloride showed association with genes reported in nephrotic syndrome (NUP205, p = 9e-7), voltage-gated channels (CACNA1E, p = 1e-6) and chloride channels (CLDN4, p = 4e-6; GABRA2, p = 1e-5), comprising a total of 47 candidate risk loci. Potassium showed mostly association with a gene involved in ion transport and polycystic kidney disease (PKD2L2, p = 1e-7), and a total of 28 candidate risk loci. Sodium showed association with genes implicated in several diseases with kidney involvement such as nephropathy (IMMP2L, P = 1e-7), Bardet-Biedl syndrome (BBSP, p = 1-e6) and ARCS1 (SH3BP2, p = 2e-6), and acting in cell polarity (PARD6G, p = 1e-6) and ion transport (ANO3, p = 3e-6), for a total of 76 candidate risk loci. In addition to these genes, other genes were already reported to be associated with cardiomyopathies, such as ABTB2 in chloride and sodium and MYOT and PRKAG2 in potassium. Conclusion This study showed novel candidate genes that may explain interindividual differences in serum electrolytes. Genes already reported to be associated with kidney abnormalities offer hints of their actual involvement in electrolyte imbalances and related disease. Moreover, associations pointing at cardiac diseases strengthen the involvement of these genes in renal electrolyte abnormalities, being one of the secondary causes of cardiomyopathies. Finally, the identification of risk loci across the three phenotypes opens the opportunity for the development of polygenic risk scores, which may benefit of an increasing number of tested samples to reach genome-wide significant signals and additional cohorts to validate the computed risk model.

Recombination map tailored to Native Hawaiians may improve robustness of genomic scans for positive selection

Recombination events establish the patterns of haplotypic structure in a population and estimates of recombination rates are used in several downstream population and statistical genetic analyses. Using suboptimal maps from distantly related populations may reduce the efficacy of genomic analyses, particularly for underrepresented populations such as the Native Hawaiians. To overcome this challenge, we constructed recombination maps using genome-wide array data from two study samples of Native Hawaiians: one reflecting the current admixed state of Native Hawaiians (NH map) and one based on individuals of enriched Polynesian ancestries (PNS map) with the potential to be used for less admixed Polynesian populations such as the Samoans. We found the recombination landscape to be less correlated with those from other continental populations (e.g. Spearman’s rho = 0.79 between PNS and CEU (Utah residents with Northern and Western European ancestry) compared to 0.92 between YRI (Yoruba in Ibadan, Nigeria) and CEU at 50 kb resolution), likely driven by the unique demographic history of the Native Hawaiians. PNS also shared the fewest recombination hotspots with other populations (e.g. 8% of hotspots shared between PNS and CEU compared to 27% of hotspots shared between YRI and CEU). We found that downstream analyses in the Native Hawaiian population, such as local ancestry inference, imputation, and IBD segment and relatedness detections, would achieve similar efficacy when using the NH map compared to an omnibus map. However, for genome scans of adaptive loci using integrated haplotype scores, we found several loci with apparent genome-wide significant signals (|Z-score|> 4) in Native Hawaiians that would not have been significant when analyzed using NH-specific maps. Population-specific recombination maps may therefore improve the robustness of haplotype-based statistics and help us better characterize the evolutionary history that may underlie Native Hawaiian-specific health conditions that persist today.

Genome-wide association study meta-analysis of blood pressure traits and hypertension in sub-Saharan African populations: an AWI-Gen study

Most hypertension-related genome-wide association studies (GWASs) focus on non-African populations, despite hypertension (a major risk factor for cardiovascular disease) being highly prevalent in Africa. The AWI-Gen study GWAS meta-analysis for blood pressure (BP)-related traits (systolic and diastolic BP, pulse pressure, mean-arterial pressure and hypertension) from three sub-Saharan African geographic regions (N = 10,775), identifies two novel genome-wide significant signals (p < 5E-08): systolic BP near P2RY1 (rs77846204; intergenic variant, p = 4.95E-08) and pulse pressure near LINC01256 (rs80141533; intergenic variant, p = 1.76E-08). No genome-wide signals are detected for the AWI-Gen GWAS meta-analysis with previous African-ancestry GWASs (UK Biobank (African), Uganda Genome Resource). Suggestive signals (p < 5E-06) are observed for all traits, with 29 SNPs associating with more than one trait and several replicating known associations. Polygenic risk scores (PRSs) developed from studies on different ancestries have limited transferability, with multi-ancestry PRS providing better prediction. This study provides insights into the genetics of BP variation in African populations.

Genetic basis of ear length in sheep breeds sampled across the region from the Middle East to the Alps.

Ear length in sheep (Ovis aries) shows a wide range of natural variation, from the absence of an outer ear structure (anotia), to small outer ears (microtia), to regular ear length. Up until now, the underlying genetics of this phenotype has been studied in four sheep breeds from China, Jordan and Italy. These studies revealed a broad range of genes significantly associated with ear length, potentially indicating genetic heterogeneity across breeds or geographic regions. In the current study, we performed genome-wide SNP genotyping and haplotype-based mapping, in a population of 340 individuals, to identify loci influencing ear length variation in additional sheep breeds from Slovenia, Croatia, Cyprus and Greece. Additionally, two previously described candidate variants were also genotyped in our mapping population. The mapping model without candidate variant genotypes revealed only one genome-wide significant signal, which was located next to HMX1 on OAR6. This region was previously described as being associated with ear length variation in the Altay and Awassi sheep breeds. The mapping model including the candidate duplication genotype near HMX1 as a fixed effect explained the phenotypic variance on OAR6 and revealed an additional genome-wide significant locus on OAR13 associated with ear length. Our results, combined with published evidence, suggest that a duplication in the evolutionarily conserved region near HMX1 is the major regulator of ear length in sheep breeds descended from a larger region from Central Asia, to the Middle East, Cyprus, Greece and to the Alps. This distribution suggests an ancient origin of the derived allele.

PSP/DEGESCO: A Progressive Supranuclear Palsy Genome‐Wide Association Study in the Spanish Population

AbstractBackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy. We genotyped all the available histopatologically confirmed PSP cases from the Spanish National Biobank Network and patients with a probable PSP diagnosis recruited from research groups linked to the Dementia Genetics Spanish Consortium (DEGESCO). Here, we present the results of the genome‐wide association study (GWAS) performed after the first stage of this project.MethodDNA samples were genotyped by the Centro Nacional de Genotipado (Santiago de Compostela, Spain) using the Affymetrix Axiom 815K Spanish biobank array. After quality control, we kept 156 histopathological (discovery) and 197 clinical (validation) PSP samples. Then, we selected 650 and 800 sex‐matched controls from GR@ACE/DEGESCO for stratified genome‐wide association of the discovery and validation sets, respectively (Table 1). We ran PC1‐4 adjusted logistic regressions with plink v2.00 and meta‐analyzed the discovery and validation sets using METAL. Finally, we meta‐analyzed our results with 36 previously reported SNPs1 reaching the largest PSP sample size to date (N = 3053).ResultWe found a strong genome‐wide significant (GWS) signal associated to the MAPT H1/H2 haplotype (rs8070723 G: OR = 3.40; 95%CI = 2.64‐4.39; p = 2.60·10−20, Figure 1) and identified a previously unreported signal in chromosome 7p13 (rs76827509 T: OR = 0.45; 95%CI = 0.35‐0.58; p = 3.09·10−10). We replicated, with nominal significance, 5 GWS SNPs reported in previous GWAS (Table 2) and found significant effects for NFASC and TOMM40. Because APOE and TOMM40 are in strong linkage disequilibrium, we also checked the effect of APOE variants. We found a protective effect (OR = 0.66; 95%CI = 0.48‐0.90; p = 9.75·10−3) of the rs429358 C allele (APOE ε4) in our dataset.ConclusionThe strong GWS signal of the H1 haplotype confirms the validity of our GWAS results2. We were able to replicate several PSP loci (Table 1). The NFASC variant reached borderline GWS significance after meta‐analysis and is a good PSP risk factor candidate. Finally, the APOE ε4 allele was protective for PSP in our cohort. The second stage of PSP/DEGESCO genotyped 218 additional PSP samples. 1 Sanchez‐Contreras, M. Y. et al. Mol. Neurodegener. (2018) 2 Höglinger, G. U. et al. in Nature Genetics (2011)

Impact of Genetic Variations on Thrombotic Risk in Saudis with Sickle Cell Disease

Background Sickle cell disease (SCD) is a Mendelian disease characterised by multigenic phenotypes. Previous reports indicated a higher rate of venous thromboembolism (VTE) in SCD patients. A number of candidate polymorphisms in certain genes (e.g. FVL, PRT, and MTHFR) were previously reported as risk factors for VTE in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlay VTE in SCD patients. Methodology A genome-wide association study involving Saudi SCD adult patients with a history of VTE (n=65) and control patients without VTE history (n=285) was performed. Genotyping used the 10x Affymetrix Axiom array which includes 683,030 markers. Results No associations were identified between the targeted single nucleotide polymorphisms (SNPs) [FVL (rs6025), PRT (rs1799963), and MTHFR (rs1801133)] and VTE episodes in SCD patients. In contrast, GWAS analysis showed two genome-wide significant signals (P&amp;lt;5×10 -8) on chromosome (Chr) 11. These SNPs, rs35390334 and rs331532, are in strong linkage equilibrium (LD, r 2=0.97). A total of 35 other markers had an association threshold of P&amp;lt;5×10 -6. Four of these variants are located in olfactory receptor genes [OR51B5 (rs147062602), OR51V1 (rs7933549), OR51A1P (rs80034548), and OR52A5 (rs2472530)]. Conclusion No association between FVL, PRT, and MTHFR genes and VTE episodes was seen in Saudis with SCD. In contrast, two markers (rs35390334 and rs331532) showed significant genome-wide associations and less significant associations (P&amp;lt;5×10 -6) were identified for 35 other variants (24 of them are located on Chr 11). Further replication of these findings is needed.

Genome-wide association study of susceptibility to hospitalised respiratory infections

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank (Stage 1). We followed-up well-imputed top signals from our Stage 1 analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts (Stage 2). We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: From our Stage 1 analysis, we report 56 signals at P&lt;5 ×10 -6, one of which was genome-wide significant ( P&lt;5 ×10 -8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in Stage 2. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our Stage 1 analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate in the meta-analysis of Stages 1 and 2. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio =2.93 [2.37-3.63], P=2.6×10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Investigating the impact of metabolic syndrome traits on telomere length: a Mendelian randomization study.

Observational studies have reported bidirectional associations between metabolic syndrome (MetS) traits and short leukocyte telomere length (LTL), a TL marker in somatic tissues and a proposed risk factor for age-related degenerative diseases. However, in Mendelian randomization studies, longer LTL has been paradoxically associated with higher MetS risk. This study investigated the hypothesis that shorter LTL might be a consequence of metabolic dysfunction. This study undertook univariable and multivariable Mendelian randomization. As instrumental variables for MetS traits, all of the genome-wide significant independent signals identified in genome-wide association studies for anthropometric, glycemic, lipid, and blood pressure traits conducted in European individuals were used. Summary-level data for LTL were obtained from a genome-wide association study conducted in the UK Biobank. Higher BMI was associated with shorter LTL (β = -0.039, 95% CI: -0.058 to -0.020, p = 5 × 10-5 ) equivalent to 1.70 years of age-related LTL change. In contrast, higher low-density lipoprotein cholesterol was associated with longer LTL (β = 0.022, 95% CI: 0.007 to 0.037, p = 0.003) equivalent to 0.96 years of age-related LTL change. Mechanistically, increased low-grade systemic inflammation, as measured by circulating C-reactive protein, and lower circulating linoleic acid levels might link higher BMI to shorter LTL. Overweight and obesity might promote the development of aging-related degenerative diseases by accelerating telomere shortening.

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection.

Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p<5×10-8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs). From a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease. Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

Genetic architecture of plasma Alzheimer disease biomarkers.

Genome-wide association studies (GWAS) of cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarker levels have identified novel genes implicated in disease risk, onset and progression. However, lumbar punctures have limited availability and may be perceived as invasive. Blood collection is readily available and well accepted, but it is not clear whether plasma biomarkers will be informative for genetic studies. Here we perform genetic analyses on concentrations of plasma amyloid-β peptides Aβ40 (n = 1,467) and Aβ42 (n = 1,484), Aβ42/40 (n = 1467) total tau (n = 504), tau phosphorylated (p-tau181; n = 1079) and neurofilament light (NfL; n = 2,058). GWAS and gene-based analysis was used to identify single variant and genes associated with plasma levels. Finally, polygenic risk score and summary statistics were used to investigate overlapping genetic architecture between plasma biomarkers, CSF biomarkers and AD risk. We found a total of six genome-wide significant signals. APOE was associated with plasma Aβ42, Aβ42/40, tau, p-tau181 and NfL. We proposed 10 candidate functional genes on the basis of 12 single nucleotide polymorphism-biomarker pairs and brain differential gene expression analysis. We found a significant genetic overlap between CSF and plasma biomarkers. We also demonstrate that it is possible to improve the specificity and sensitivity of these biomarkers, when genetic variants regulating protein levels are included in the model. This current study using plasma biomarker levels as quantitative traits can be critical to identification of novel genes that impact AD and more accurate interpretation of plasma biomarker levels.

The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes

Aims/hypothesisThe Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population.MethodsWe evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort.ResultsCompared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10−9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance.Conclusions/interpretationOur results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores.Data availabilityFull summary statistics are available through the Common Metabolic Diseases Knowledge Portal (https://t2d.hugeamp.org/downloads.html) and through the GWAS catalog (https://www.ebi.ac.uk/gwas/, accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog (https://www.pgscatalog.org, publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445).Graphical abstract

Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program.

Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's<0.05). European ancestry (EA) analysis identified GWS loci on chromosomes 6 and 9, as well as GWS gene associations in EXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (rG = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; rG = 0.78; p = 1.98e-95) and major depressive disorder (MDD; rG = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors.

Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common control subjects

Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures.

Genome-wide association study of abdominal MRI-measured visceral fat: The multiethnic cohort adiposity phenotype study.

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements.

Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans.

This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions. We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes. Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p=2.2×10-5 ) and 18q21.33 (p=1.2×10-5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2. Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus. We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.

Variation at the LRRK2 locus determines the rate of disease progression in pro- gressive supranuclear palsy

BackgroundThe genetic basis of variation in the rate of disease progression in primary tauopathies is poorly understood. Here, we have conducted a genome-wide association study (GWAS) of Progressive Supranuclear Palsy cases using survival as a marker of disease progression.MethodsTwo independent, deeply-phenotyped, PSP cohorts of European ancestry underwent genotyp- ing and SNP imputation. Standard data quality control steps were used, including a MAF threshold of 1%. We used a cox-proportional hazards survival model GWAS that adjusted for sex, age at motor symptom onset, PSP phenotype and ethnicity (first three principal components).Results1,001 PSP cases (2011 case-control GWAS, n=424; UCL PSP cohort, n=577) and 4,817,946 SNPs passed quality control steps and were available for analysis. We found a genome-wide significant signal on chromosome 12 with the lead SNP identified as rs2242367 (hazard ratio = 2.24, p-value = 7.5x10-10). This signal replicated when each independent cohort was analysed separately. The risk allele at this SNP was associated with a 1 year reduction in survival. eQTL analyses revealed that rs2242367 and its tagging SNPs are eQTLs for LRRK2 expression in whole blood and brain.ConclusionsWe hypothesise that the whole blood eQTL signal may impact on monocyte-derived micro- glia-like cells and that increased LRRK2 expression may result in a reactive microglia-induced pro-inflam- matory state which drives ongoing accumulation of misfolded tau protein and clinical disease progression.e.jabbari@ucl.ac.uk

Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium.

Background and ObjectivesConsiderable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.MethodsA meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC).ResultsThe COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8).DiscussionOur study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset.

Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.

Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.