ED has an age-dependent prevalence, with 20%–40% of men aged 60–69 years affected.
The genetic architecture of ED remains poorly understood, owing in part to a paucity of well-powered genetic association studies. Discovery of such genetic associations can be valuable for elucidating the etiology of ED and can provide genetic support for potential new therapies.
a lack of primary care data availability in UKBB, and intercultural differences, including “social desirability” bias.
Importantly, we note that the assessment of exposure-outcome relationships remains valid, despite the prevalence likely not being representative of the general population prevalence.
The puberty timing-associated SNP in the MCHR2-SIM1 region (rs9321659; ∼500 kb from rs57989773) was not in LD with our lead variant (r2 = 0.003, D’ = 0.095) and was not associated with ED (p = 0.32) in our meta-analysis, suggesting that the ED locus represents an independent signal.
for the lead variant rs57989773 and its proxies (r2 > 0.8, determined using HaploReg v.4.1) (Supplemental Material and Methods). Enhancer marks in several tissues, including embryonic stem cells, mesenchymal stem cells, and endothelial cells, indicated that the ED-associated interval lies within a regulatory locus (Figure 2A; Table S6).
showed that MCHR2 and SIM1 were in the same topologically associated domain (TAD) as the ED-associated variants, with high contact probabilities (referring to the relative number of times that reads in two 40-kb bins were sequenced together) between the ED-associated interval and SIM1 (Figures 2B and S2). This observation was further confirmed in endothelial precursor cells,
where Capture Hi-C revealed strong connections between the MCHR2-SIM1 intergenic region and the SIM1 promoter (Figure 2C), pointing toward SIM1 as a likely causal gene at this locus.
to examine in vivo expression data for non-coding elements within the MCHR2-SIM1 locus. A regulatory human element (hs576), located 30-kb downstream of the ED-associated interval, seems to drive in vivo enhancer activity specifically in the midbrain (mesencephalon) and cranial nerve in mouse embryos (Figure 2D). This long-range enhancer close to ED-associated variants recapitulated aspects of SIM1 expression (Figure 2D), further suggesting that the ED-associated interval belongs to the regulatory landscape of SIM1. Taken together these data suggest that the MCHR2-SIM1 intergenic region harbors a neuronal enhancer and that SIM1 is functionally connected to the ED-associated region.
Rare variants in SIM1 have been linked to a phenotype of severe obesity and autonomic dysfunction,
including lower blood pressure. A summary of the variant-phenotype associations at the 6q16 locus in human and rodent models is shown in Table S7. Post hoc analysis of association of rs57989773 with autonomic traits showed nominal association with syncope, orthostatic hypotension, and urinary incontinence (Figure S3). The effects on blood pressure and adiposity seen in individuals with rare coding variants in SIM1 are recapitulated in individuals harboring the common ED-risk variants at the 6q16.3 locus (Figure 1D), suggesting that SIM1 is the causal gene at the ED-risk locus. SIM1-expressing neurons also play an important role in the central regulation of male sexual behavior as mice that lack the melanocortin receptor 4 (encoded by MC4R) specifically in SIM1-expressing neurons show impaired sexual performance on mounting, intromission, and ejaculation.
Thus, hypothalamic dysregulation of SIM1 could present a potential mechanism for the effect of the MCHR2-SIM1 locus on ED.
predicts that the pseudogene transcript would interact with the ARG2 protein, with probabilities of 0.70–0.77. Arginine 2 is involved in nitric oxide production and has a previously established role in erectile dysfunction.
GTEx expression data
demonstrated highest mean expression in adipose tissue, with detectable levels in testis, fibroblasts, and brain. Expression was relatively low in all tissues, however, and there was no evidence that any SNPs associated with the top ED signal were eQTLs for the ARG2 pseudogene or ARG2 itself.
tools to identify gene-set, tissue-type, and functional enrichments. In DEPICT, the top two prioritized gene-sets were “regulation of cellular component size” and “regulation of protein polymerization,” whereas the top two associated tissue/cell types were “cartilage” and “mesenchymal stem cells.” None of the DEPICT enrichments reached an FDR threshold of 5% (Tables S8–S10). GARFIELD analyses, which assesses enrichment of GWAS signals in regulatory or functional regions in different cell types, also did not yield any statistically significant enrichments, therefore limiting the utility of these approaches in this case.
including type 2 diabetes mellitus (T2D), hypertension, and smoking. To further evaluate these associations, we first conducted LD score regression
to evaluate the genetic correlation of ED with a range of traits. LD score regression identified ED to share the greatest genetic correlation with T2D, limb fat mass, and whole-body fat mass (FDR-adjusted p values < 0.05; Table S11).
(MR) analyses to evaluate the potential causal role of nine pre-defined cardiometabolic traits on ED risk (selected based on previous observational evidence linking such traits to ED risk
), i.e., T2D, insulin resistance, systolic blood pressure, LDL cholesterol, smoking heaviness, alcohol consumption, body mass index, coronary heart disease, and educational attainment (Tables S12–S15). MR identified genetic risk to T2D to be causally implicated in ED: each 1-log higher genetic risk of T2D was found to increase risk of ED with an OR of 1.11 (95% CI 1.05–1.17, p = 3.5 × 10−4, which met our a priori Bonferroni-corrected significance threshold of 0.0056 [0.05/9]), with insulin resistance likely representing a mediating pathway
(OR 1.36 per 1 standard deviation genetically elevated insulin resistance, 95% CI 1.01–1.84, p = 0.042). Sensitivity analyses were conducted to evaluate the robustness of the T2D-ED estimate (Figure S5, Table S13), including weighted median analyses (OR 1.12, 95% CI 1.02–1.23, p = 0.0230), leave-one-out analysis for all variants (which indicated that no single SNP in the instrument unduly influenced the overall value derived from the summary IVW estimate
), and a funnel plot (showing a symmetrical distribution of single-SNP IV estimates around the summary IVW causal estimate). The MR-Egger regression (intercept p = 0.35) provided no evidence to support the presence of directional pleiotropy as a potential source of confounding.
ED is most commonly treated using phosphodiesterase 5 (PDE5) inhibitors such as sildenafil. To identify potential phenotypic effects of PDE5 inhibition (e.g., to predict side effects or opportunities for repurposing), we looked for variants in or around PDE5A, encoding PDE5, which showed association with the ED phenotype. Of all 4,670 variants within a 1 Mb window of PDE5A (chromosome 4:119,915,550–121,050,146 as per GRCh37/hg19), the variant with the strongest association was rs115571325, 26 kb upstream of PDE5A (ORMeta 1.25, nominal p value = 8.46 × 10−4; Bonferroni-corrected threshold [0.05/4,670] = 1.07 × 10−5; Figure S6). Given the weak association with ED, we did not evaluate this variant in further detail.
Further research is needed to explore the extent to which drugs used in the treatment of T2D might be repurposed for the treatment of ED. Lack of evidence for a causal effect of BMI on ED risk in MR analysis (using multiple SNPs across the genome) suggests that the association of the lead SNP (rs57989773) with BMI arises from pleiotropy and that the association of this variant with ED risk is independent of its association with adiposity.