Wednesday, September 23, 2015

Pain: OPRM1 & The Ancestral Contribution [Review]

A paper by Soto & Catanesi assessing genetic variation in the μ (mu) opioid receptor gene (OPRM1) was published in May 2015. OPRM1 contributes to the structure of the μ opioid receptor (MOR), one of three major opioid receptor types which broadly contribute to pain sensation, addiction, ion influx into cells and a host of other functions [1]. 

WHO Pain Ladder (courtesy of
Opioid receptors are of interest to medical researchers due to the varying specificity of receptor agonism (activation) by conventional treatments (e.g. tramadol has a higher affinity to MORs than others [2]). Additionally, opioid receptor antagonists are widely used in pain management (as directed by the World Health Organisation's classic "pain management ladder", figure opposite [3]). As such, understanding the structure of opioid receptor characteristics between individuals could theoretically fine-tune the ideal pharmaceutical agents to be used in specific situations, such as in palliative or acute care, as well as narcotic or surgical rehabilitation (in effect stratified or personalised medicine).

Although the paper indicates contradiction in our current data regarding the most studied SNP to date (rs1799971, linked to the A118G polymorphism), others residing within or near OPRM1 are postulated to have an effect on MOR function.

OPRM1 from a population genetics perspective is of interest through the observation in numerous older studies (listed within paper) that show differing A118G polymorphism frequencies across various world populations. The authors extended these findings by including the HapMap world database with their own Argentinian samples to determine whether OPRM1 SNP variants correlated with ancestral background. Establishing the polymorphic frequency among Argentinians appears to be a secondary aim here.

The authors of this paper concluded that Sub-Saharan African, West and East Eurasian ancestral status coincides with OPRM1 polymorphism status in the several SNPs examined (through the use of Fst and AMOVA). However, they noted that no such clustering was observed between West Eurasians (Europeans) and American populations (mixed Argentinian and Mexican samples). This was taken to indicate extensive gene flow from European colonists had made a massive contribution to the polymorphic status at this gene. 

Another possibility not highlighted in the paper is that the native Amerindian population of pre-colonial America had similar OPRM1 polymorphic status as modern West Eurasians. In light of the recent findings supporting sizeable mutual prehistoric ancestry between these two populations through a conceptual "Ancestral North Eurasian" (ANE) component (Raghavan et al., see below) [4], the OPRM1 congruity between Amerind-European mixed modern Americans and Europeans could partially be attributed to the proposed ANE-containing migratory events. [4] 

Estimated Shared Drift Heat Map with MA1 (Raghavan et al.)

Overall, Soto & Catanesi provide us with a good summary of the population structure that can be directly observed through OPRM1 gene polymorphism variation and support earlier work indicating a correlation with ancestry. It would have furnished their discussion better had some exploration of recent developments in archaeogenetics been undertaken. Their assertion of complete OPRM1 SNP status replacement among Amerind-European admixed American individuals is of course possible, but no evidence is provided that categorically dismisses commonality between Europeans and Amerindians on this genomic region as at least partially responsible for the observation.

Human population genetic structure detected by pain-related mu opioid receptor gene polymorphisms.
López Soto EJ, Catanesi CI. Genet Mol Biol. 2015 May;38(2):152-5. doi: 10.1590/S1415-4757382220140299. Epub 2015 May 1.
"Several single nucleotide polymorphisms (SNPs) in the Mu Opioid Receptor gene (OPRM1) have been identified and associated with a wide variety of clinical phenotypes related both to pain sensitivity and analgesic requirements. The A118G and other potentially functional OPRM1 SNPs show significant differences in their allele distributions among populations. However, they have not been properly addressed in a population genetic analysis. Population stratification could lead to erroneous conclusions when they are not taken into account in association studies. The aim of our study was to analyze OPRM1 SNP variability by comparing population samples of the International Hap Map database and to analyze a new population sample from the city of Corrientes, Argentina. The results confirm that OPRM1 SNP variability differs among human populations and displays a clear ancestry genetic structure, with three population clusters: Africa, Asia, and Europe-America."

1. Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Curr Drug Targets. 2012 Feb;13(2):230-46.

2. Dayer P, Desmeules J, Collart L. [Pharmacology of tramadol]. Drugs. 1997;53 Suppl 2:18-24. [Article in French]

3. WHO | WHO's cancer pain ladder for adults. [Last Retrieved 22/09/2015]: 

4. Raghavan M, Skoglund P, Graf KE, Metspalu M, Albrechtsen A. Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans. Nature. 2014 Jan 2;505(7481):87-91. doi: 10.1038/nature12736. Epub 2013 Nov 20.