The genetic basis of addictive disorders.

Heritability (weighted means and ranges) of 10 addictive disorders: hallucinogens, cannabis, stimulants, sedatives, opiates, and cocaine dependence or abuse; alcohol dependence; smoking; caffeine consumption or heavy use; pathologic gambling. Weighted heritability (h2) means were computed using data from large surveys of adult twins. (Adapted from Goldman D, Oroszi G, Ducci F. The genetics of addictions: uncovering the genes. Nat Rev Genet 2005;6(7):521–32.)

Impact of psychiatric disease status, smoking behavior, and Asp398Asn influence on dorsal anterior cingulate–right ventral striatum functional connectivity. (A) Asn398 carriers as compared to Asp398/Asp398 homozygotes displayed reduced connectivity. Independently from genotype effect, reduced connectivity was also found in smokers (SK) vs nonsmokers (NS) and in psychiatric patients as compared to healthy participants. (B) Nicotine craving was negatively correlated with functional connectivity of dorsal anterior cingulate–ventral stria-tum in both smokers with and without psychiatric illnesses. (Adapted from Hong LE, Hodgkinson CA, Yang Y, et al. A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction. Proc Natl Acad Sci U S A 2010;107(30):13509–14.)

Rare and common MAOA variants. (A) Dutch pedigree with eight males affected by Brunner syndrome, X-linked behavioral dyscontrol caused by an MAOA stop codon (C936T). (B) The MAOA-linked polymorphic region (MAOA–LPR) is a common 30-bp VNTR located approximately 1.2 kb upstream from the MAOA start codon and within the transcriptional control region. The three-repeat allele is transcribed less efficiently, leading to lower MAOA enzyme activity and behavioral consequences. ([A] Adapted from Brunner HG, Nelen M, Breakefield XO, et al. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 1993;262(5133):578–80.)

Genetic complexity in unrelated individuals: epistasis and heterogeneity. Each risk allele is represented as a puzzle piece of different color or shape. Black circles indicate affected individuals and empty circles denote unaffected individuals. (Adapted from Gold man D, Oroszi G, Ducci F. The genetics of addictions: uncovering the genes. Nat Rev Genet 2005;6(7):521–32.)

Genetic complexity and twin concordance: epistasis and heterogeneity. Each risk allele is represented as a puzzle piece of different color or shape. Members of twin pairs are represented by squares. Black squares indicate affected individuals and empty squares denote unaffected individuals. (Adapted from Goldman D, Oroszi G, Ducci F. The genetics of addictions: uncovering the genes. Nat Rev Genet 2005;6(7):521–32.)

MZ/DZ twin concordance ratios for 10 addictions. MZ/DZ ratios tend to converge on two, inconsistent with the epistatic model (see text). (Adapted from Goldman D, Oroszi G, Ducci F. The genetics of addictions: uncovering the genes. Nat Rev Genet 2005;6(7):521–32.)

Additive effects of the TTC12–ANKK1–DRD2 and CHRNA5–CHRNA3–CHRNB4 gene clusters on smoking behavior in adolescence and adulthood. Risk of heavy smoking increases linearly with the number of risk alleles at the two loci. Odds ratios (OR) and 95% confidence intervals (CI). (Adapted from Ducci F, Kaakinen M, Pouta A, et al. TTC12–ANKK1–DRD2 and CHRNA5–CHRNA3–CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood. Biol Psychiatry 2011;69(7):650–60.)

Functional polymorphisms in ethanol metabolism: ADH1B His48Arg and ALDH2 Glu487Lys. Higher activity of ADH1B, conferred by Arg48, or lower activity of ALDH2, conferred by Lys487, leads to accumulation of acetaldehyde after alcohol consumption and the flushing reaction.

Geographic distributions of ALDH2 Lys487 and esophageal cancer. The Lys487 allele is highly abundant in Southeast Asia but virtually absent in Europeans, Africans, and Amerindians. Southeast Asia is also an epidemiologic hotspot for esophageal cancer, consistent with genetic epidemiologic studies that have connected risk of esophageal cancer to moderate consumption of alcohol in carriers of the Lys487 allele. Acetaldehyde is a carcinogen.58 (Adapted from Li H, Borinskaya S, Yoshimura K, et al. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet 2009;73(Pt 3):335–45; with permission.)

The serotonin-transporter-linked polymorphic region. The human serotonin transporter promoter has a common VNTR termed HTTLPR. The major alleles within this VNTR, namelyL (long) and S (short), differ in number of copies of a 20-bpto23-bp imperfect repeat. The L allele, which leads to increased transcription efficiency, has 16 copies of the repeat and the S allele has 14 copies. Further, a relatively common, functional A > G SNP within the L allele leads to an LG allele functionally equivalent to the S allele. (Data from Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274(5292):1527-31; and Hu XZ, Lipsky RH, Zhu G, et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive compulsive disorder. Am J Hum Genet 2006;78(5):815–26.)

Association between smoking (number of cigarettes smoked per day, CPD) and genetic variation within the CHRNA5-CHRNA3-CHRNB4 gene-cluster on c15q25. (A) In the Manhattan plot, level of significance (–Log P value) of association to SNPs covering 22 autosomes is shown. SNPs reaching genome-wide significance (P<10−8) are in green. (B) The chromosome 15 region contains the CHRNA5-CHRNA3-CHRNB4 gene cluster. (C) The most significant SNP within this region is rs1051730, which correlates highly with Asp398Asn. (Data from Liu JZ, Tozzi F, Waterworth DM, et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 2010;42(5):436-40; Hong LE, Gu H, Yang Y, et al. Association of nicotine addiction and nicotine's actions with separate cingulate cortex functional circuits. Arch Gen Psychiatry 2009;66(4):431–41.)