Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11018-11023. doi: 10.1073/pnas.1809872115. Epub 2018 Oct 8.

Genetic variation in the SIM1 locus is associated with erectile dysfunction.

Author information

1
Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612; eric.jorgenson@kp.org Stephen.vandeneeden@kp.org.
2
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158.
3
Institute for Human Genetics, University of California, San Francisco, CA 94158.
4
Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195.
5
Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612.
6
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158.
7
Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT 84132.
8
Deparment of Urology, University of Washington School of Medicine, Seattle, WA 98195.

Abstract

Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function.

KEYWORDS:

SIM1; erectile dysfunction; genetic; genome-wide association; melanocortin

PMID:
30297428
PMCID:
PMC6205494
DOI:
10.1073/pnas.1809872115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center