The Genetic Basis of Addictive Disorders
Section snippets
Heritability of Addictions
Evidence from family, adoption, and twin studies converges on the relevance of genetic factors in the development of addictions including SUDs and gambling.7, 8, 9, 10, 11, 12, 13 Weighted mean heritabilities for addictions computed from several studies of large cohorts of twins are shown in Fig. 1.14 Heritability is lowest for hallucinogens (0.39) and highest for cocaine (0.72).
Heritability estimates are usually higher for addiction than for substance use; however, “no pathologic drug use” and
Interplay Between Genetic and Enviromental Factors
The gene (nature) versus environment (nurture) debate represented a misguided and polarizing, dichotomy. Genetic and environmental factors interact in complex ways37 but there are two main types of violations of gene–environment independence: gene × environment interaction and gene × environment correlation.
Gene × environment correlation (rGE) occurs when genotype correlates (r) with probability of exposure to an environmental factor. Twin studies can address the existence of rGE by measuring
SLC6A4
The serotonin transporter (SLC6A4) regulates synaptic levels of serotonin, a neurotransmitter involved in the regulation of mood, appetite, and impulse control. Reflecting these diverse actions, serotonin-specific reuptake inhibitors are the most commonly prescribed category of medications for mental illness. The serotonin transporter gene SLC6A4 has a common variable number tandem repeat (VNTR) in its promoter region (HTTLPR) (Fig. 8) that is the most frequently studied locus in psychiatric
Genome-Wide Association Studies
As compared to candidate gene studies, genome-wide association studies (GWAS) have the advantage of covering the entire genome in an hypothesis-free way, and the methodology is powerful for detecting relatively common alleles (minor allele frequency [MAF] >5%) of moderate effect. As discussed later, the impact of less common variants cannot be studied by using the current GWAS arrays and requires sequencing strategies. Another advantage of GWAS is that the same genotyping arrays are obtained in
Rare and Common Variants
The focus of genetic studies of addiction, as well as other common disorders, has been common genetic variants with MAF greater than 1%, and usually greater than 5%. The idea behind these studies is the common disease/common variant (CD/CV) hypothesis according to which common alleles of ancient origin and with small to moderate effect lead to susceptibility to common disorders. However, recent evidence suggests that rare variants of stronger effect might substantially contribute to the genetic
HTR2B
An HTR2B stop codon was linked to severe impulsive aggression, ASPD, and alcoholism, with an effect that appeared to be modulated by stress, alcohol consumption, and hormones. Unlike the MAOA stop codon, the HTR2B stop codon is recurrent, being found in at least 100,000 individuals, but population-restricted.
The HTR2B gene, located on chromosome 2 (2q36.3–q37.1), encodes the serotonin 2B receptor, a G protein–coupled receptor. Serotonin 2B receptors are widely expressed in the human brain. A
Classification and Treatment of Addictions
Current nosology of addictions limits both clinicians and researchers. The diagnoses are syndromic (based on clusters of symptoms and clinical course rather than etiologically based).132 In addition, diagnoses are categorical, assuming a cutoff between normal and abnormal, although many of the problems associated with addiction are found in people who fall below the disease-associated threshold.133 As discussed, twin studies have detected evidence of etiologic factors shared with other
Summary
Addictions are common, chronic, and relapsing diseases that develop through a multistep process. The impact of addictions on morbidity and mortality is high worldwide. Twin studies have shown that the heritability of addictions ranges from 0.39 (hallucinogens) to 0.72 (cocaine). Twin studies indicate that genes influence each stage from initiation to addiction, although the genetic determinants may differ. Addictions are by definition the result of gene × environment interaction. These
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