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Left-handedness Predicts Alcohol Addiction Via Genetic Interaction and Subsequent Neurological Lateralization in the Dominant Auditory Cortex

 

I) Scientific Problem

The relatively broad gap in research regarding the quantification of neuro-physiological and genomic signals associated with left-handedness that can predict the susceptibility of a patient to alcohol addiction.

 

II) Purpose

To determine the genetic/neurological linkage between left-handed processing and alcohol addiction.

 

III) Background/Intro

The medical sequelae associated with alcohol addiction continue to pose a significant burden to healthcare and society alike. Significant health pathologies related to substance abuse often manifest themselves in a number of different physical and psychological conditions including anxiety, depression, motor vehicle accidents, high/low blood pressure, physical dependence, seizures, and even death1. Additionally, federal spending in relation to drug-related incarceration and publically available detoxification and treatment options for those without healthcare continues to be unprecedented2. Alcohol addiction, therefore, poses a threat not only to the health of the individual user, but also to the overall welfare of society. Thus, a preventative means to adequately recognize genetic, and thereby, neurological processes that can predict the likelihood of certain patient populations to develop this debilitating disease would be highly desirable.

 

After controlling for a number of confounders, recent studies show that left-handers, in fact, do drink more often than right-handed subjects3. Additionally, an increased frequency of left-handedness and ambilateraliry has been found to be associated with a variety of neuropathological syndromes such as cerebral palsy, epilepsy, mental retardation, and language problems, as well as an increased likelihood to develop schizophrenia, delinquency, dyslexia, and Crohn's disease all as a result of birth complications associated with anoxia. Interestingly, these studies also assert that left hand dominance as a result of anoxia may be a precursor of alcoholism4,5,6. Genetically, alcohol addiction has been found to be strongly polygenic, where each allelic variant contributes in a small, additive fashion to alcohol addiction vulnerability. Interestingly, although genetic heterogeneity exists, there is substantial convergence of Genome Wide Association Study (GWAS) signals on particular genes7. Handedness, however, demonstrates an absence of a strong genetic factor. However, it is widely believed that handedness is not a matter of choice or learning, suggesting that there are many relatively weak genetic factors in handedness as opposed to any strong factors8. Thus, according to the increased prevalence of alcohol addiction in left-handers in conjunction with the notion that each condition is regulated by a number of different genes, it is plausible to suggest that one or more of these genes are operating simultaneously to increase the predisposition to drug or alcohol addiction in the left handed patient population.

 

Scientists whom have studied stroke patients demonstrated further evidence that may support the genetically rooted linkage between handedness and addiction when they reported that an injury to a specific part of the auditory cortex could instantly and permanently break an addiction9. Similarly, unique brain activity specific to handedness has also recently been described in the auditory cortex, as distinctive unilateral projections were found in the inferior part of the auditory cortex, specifically in the insula, of the dominant hemisphere according to the subject's handedness10. Thus, due to the localization of brain signals associated with alcohol addiction and handedness to auditory cortex, it is possible to hypothesize that both traits may be spatially linked to the insula in the auditory cortex of the dominant hemisphere. This provides compelling evidence that certain genes may converge to control neurological processing associated with left-handedness and alcohol addiction. 

 

IV) Hypothesis

A genetic linkage associated with left-handedness can predict alcohol addiction via neurological processing and localization to the auditory cortex of the dominant brain hemisphere. 

 

V) Experimental Methods

To assess our hypothesis, we plan to conduct a genome-wide association study (GWAS) to compare the associations between single-nucleotide polymorphisms (SNPs) in different groups of experimental DNA outlined as follows: Group 1 will consist of DNA reflecting phenotypically right handed individuals with no history of substance abuse (Rx), Group 2 will consist of DNA corresponding to phenotypically right handed individuals with a history of substance abuse issues (RSA), Group 3 DNA will reflect phenotypically left handed subjects without a history of substance abuse (Lx), while Group 4 will be DNA collected from phenotypically left handed patients with a history of substance abuse (LSA). This strategy is illustrated in Appendix I (Table I). Groups 1, 3 and 4 will serve as control groups, whereas group 4 will be our experimental group. Using SNP arrays, we will be able to visualize both the genomic location and the level of association of each trait, which will illuminate the strongly associated risk loci. For example, we will be able to quantitatively visualize the extent to which genetic variants associated with alcohol addiction are found in individuals that are either left or right handed. We also plan to use the GWAS to screen for polymorphic genomic association, that is the existence of multiple genes controlling alcohol addiction that may be linked to left-handedness. This could further reveal specific genes, which are known to contribute to the development of alcohol addiction, that are also associated with genes that result in left-handedness.

 

We will then conduct a second experiment to observe the spatial localization of neurological signals associated with each of the four groups, with the purpose of determining an overlap of signaling in a particular location. Utilizing functional MRIs (fMRIs) we will monitor brain activity by detecting associated changes in blood flow to the auditory cortex. In this experiment, we will monitor the four aforementioned groups via fMRI whist consuming alcohol and performing written tasks to observe the different patterns in brain activation. These results will be quantified using blood-oxygen-level dependent (BOLD) contrast and thresholding. 

 

VI) Outcomes

Outcomes of the GWAS would expectantly elucidate one or more genes working in symphony to control both the occurrence of alcohol addiction and expression of left-handedness. fMRI results would predictably reveal a convergence in neurological signaling to the insula of the auditory cortex in the LSA group. Conversely, we would not expect to see this convergence of signaling in the Rx, RSA, or the Lx groups. This would demonstrate a specific, genetically rooted, neurological linkage between left-handedness and alcohol addiction to the insula in the dominant auditory cortex. 

 

VII) Caveats

There are a number of caveats that would make this scientific problem particularly challenging to assess. First and foremost, pilot studies often require a basis of experimental data, typically obtained utilizing an animal model. However, constructing an animal model that allows for the manipulation of right or left handed dexterity would be difficult, if not impossible. Thus, experimentation would need to be conducted clinically, raising a new level of procedural and funding complications. Secondly, this would be a difficult experiment to control, as there are a number of confounding societal and biological variables that could account for both handedness and alcohol addiction alone. Thus, controlling the study in the clinic would be exceedingly difficult, as a number of moral/ethical questions could be raised, particularly in regards to the monitoring of alcohol consumption in patients who are substance-dependent.   

  

VIII) References

 

  • Burke PJ, O'Sullivan J, Vaughan BL."Adolescent substance use: brief interventions by emergency care providers". Pediatr Emerg Care 21 (11): 770–6. 2005.

  • Prieto L. Labelled drug-related public expenditure in relation to gross domestic product (gdp) in Europe: A luxury good? Substance Abuse Treatment, Prevention, and Policy 5:9. 2010.

  • Denny K. “Handedness and drinking behaviour”. British Journal of Health Psychology 15 (2): 386-395. 2011. 

  • Bakan, P. Handedness and birth order. Nature, 1971, 229, 195

  • Bakan, P. Handedness and birth stress. (Unpublished manuscript, 1972)

  • Montagu, M. Prenatal influences. Springfield, 111: Thomas, 1962.

  • Hall FS, Drgonova J, Jain S, Uhl GR. Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong? Pharmacol Ther. 2013 Dec;140(3):267-79.

  • Armour J AL, Davison A, McManus I C. Genome-wide association study of handedness excludes simple genetic models. Heredity 2013.

  • Naqvi1 NH, Rudrauf D, Damasio H, Bechara1 A. Damage to the Insula Disrupts Addiction to Cigarette Smoking. Science. 2007 Jan; 315: 531-534.

  • Fauriona A, Cerfa B, Van De Moortelec F, Lobelc E, Mac Leoda P, Le Bihanc D. Human taste cortical areas studied with functional magnetic resonance imaging: evidence of functional lateralization related to handedness. Neuroscience Letters. 1999 Dec; 277(3):189-192.

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