Genetic variation in the SIM1 locus is associated with erectile dysfunction

Authors Jorgenson, Matharu, Palmer et al.

Review Date October 2018

Citation PNAS. 2018. pii: 201809872


Erectile dysfunction (ED) is common in older men, and in Australia one in 5 men over the age of 40 report moderate to severe ED.[1] ED can have physical or psychological causes and a range of factors including high blood pressure, diabetes, obesity, high cholesterol, smoking, sleep apnoea and lower urinary tract symptoms contribute to the risk (2, 3, 4). ED is strongly associated with symptoms of depression and anxiety, which have a bidirectional relationship.[2, 3, 4]

Given the link between ED and chronic, particularly cardiovascular, disease, there is a strong need to understand the aetiology of ED in its different forms so that it may be better treated. Up to one-third of ED risk may be related to genetic inheritance, independent of known ED risk factors.[5] However to date, no specific changes in the genome have been identified that are associated with ED. In this study, the researchers looked across thousands of common gene variations already mapped in the human genome (single nucleotide polymorphisms [SNPs]) to see if any are linked to the presence of ED.


To identify genetic risk factors for ED through large-scale population genome analyses of men in the US and the UK.


A genome-wide association study (GWAS) was undertaken in a large population of men enrolled in the Genetic Epidemiology Research in Adult Health and Ageing (GERA) study (Kaiser Permanente, Northern California). The cohort was ethnically diverse including non-Hispanic white, Hispanic/Latino, East Asian and African American populations. To define cases of ED, researchers obtained self-reported ED symptoms via a health questionnaire, and clinical data via electronic health records and filled prescriptions for ED medications. GWAS was performed for ED across 665,000 SNPs in the DNA of 36,649 men.

GWAS results were subsequently validated in an independent population of 222,358 men in the UK (UK Biobank). These men were aged between 40 and 69 years and represented five ethnicity groups, and were grouped into cases and controls based on a clinical record of ED or self-reported use of ED medications.


In the GERA cohort, there were 14,215 cases of ED and 22,434 controls. Factors more prevalent in cases versus controls were diabetes (29.8% vs 14.6%) and former smoking (53.1% vs 37.2%), and BMI was slightly higher (mean [SD]; 27.4[4.70] vs 26.9[4.3]), however men with ED were older (mean [SD]; 68.9[10.8] vs 56.1[11.4]).

The GWAS identified five SNPs on chromosome 5 that were significantly associated with ED. The same five SNPs were also significantly associated with ED in the UK cohort, validating the initial findings. These SNPs were located in a region of DNA near the SIM1 gene.

One evolutionary conserved SNP (rs17185536-C/T) was selected for further investigation. The rs17185536-T version was strongly associated with increased risk of ED, independent of the presence of known risk factors (e.g. BMI, diabetes). The strongest association with ED occurred in men aged 50-59 years old (odds ratio 1.32, 95% CI 1.24-1.41).

This SNP was located upstream of the SIM1 gene in a region that interacts with the SIM1 gene promoter. The presence of the rs17185536-T allele was shown to enhance the activity of the SIM1 gene.


The SIM1 gene is involved in the leptin-melanocortin pathway, which regulates aspects of body weight and sexual function. Given that the study did not find BMI to be associated with the presence of the SNP (rs17185536-T) in ED cases, the authors hypothesised that the increased risk may occur through a direct effect on sexual function. They speculated that the presence of this SNP may cause differing SIM1 activity in neurons that control erectile function.

This study identifies a previously unknown gene pathway that could contribute to the cause of ED in some men. Future studies will be needed to better understand the mechanism by which the SIM1 gene regulates erectile function, but this presents potential new areas for future ED therapies.

Points to Note

• SNP rs17185536-T was associated with increased risk of ED by 25-36% among non-Hispanic white, Hispanic/Latino and African American ethnicities, but was not associated with significant risk in East Asian population where this allele infrequently occurs.

• There was an increasing effect of SNP rs17185536-T with the severity of self-reported ED. Men reporting being able to have satisfactory erections ‘usually’, ‘sometimes’, or ‘never’ had ED odds ratios of 1.15, 1.3, and 1.41, respectively.


1.Holden CA, McLachlan RI, Pitts M, et al. (2005) Lancet. 366(9481):218-224. Link

2. Schlichthorst M, Sanci LA and Hocking JS (2016) BMC Public Health. 16(Suppl 3):1043. Link

3. Martin S, Atlantis E, Wilson D, et al. (2012) J Sex Med. 9(8):2093-2103. Link

4. Weber MF, Smith DP, O’Connell DL, et al. (2013) Med J Aust. 199(2):107-111. Link

5. Fischer ME, Vitek ME, Hedeker D, et al. (2004) Arch Intern Med. 164(2):165-168. Link

Website: https://www.ncbi.nlm.nih.gov/pubmed/30297428

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