Identifying genes for alcohol and drug sensitivity: recent progress and future directions

doi:10.1016/S0166-2236(99)01393-4

Trends in Neurosciences

Volume 22, Issue 4, 1 April 1999, Pages 173-179

https://doi.org/10.1016/S0166-2236(99)01393-4 Get rights and content

Abstract

New methods for identifying chromosomal regions containing genes that affect murine responses to alcohol and drugs have been used to identify many provisional quantitative trait loci (QTLs) since 1991. By 1998, 24 QTLs had been definitively mapped (P<5×10⁻⁵) to specific murine chromosomes, which indicates the presence of a relevant gene or genes at each location. The syntenic (homologous) region of the human genome for these genes is often known. For many mapped QTLs, candidate genes with relevant neurobiological function lie within the mapped region. Data that implicate candidate genes for specific responses include studies of knockout animals. Current strategies for gene identification include the use of congenic strains containing QTL regions introduced from another strain. There is increasing emphasis on gene–gene and gene–environment interactions in such studies.

Section snippets

Mapping methods

Many inbred strains of mice are available for genetic mapping experiments. Within an inbred strain, same-sex animals are essentially monozygotic twins and, furthermore, have two identical copies of a single allele at each locus. When strains are crossed, the F₁ generation is heterozygous at all genes that differ in the parents. Crossing F₁ mice to obtain an F₂, or backcrossing an F₁ to one of the parental inbreds, produces a generation that segregates genetically. Initial identification of QTLs

Acute alcohol- and pentobarbitol-withdrawal convulsions

D2-strain mice are known to express severe alcohol-withdrawal convulsions, whereas B6-strain mice have a much milder withdrawal reaction23, 24. Using three populations derived from B6 and D2 (BXD RI strains, an F₂ cross and selected lines), Buck et al.¹¹ mapped three QTLs that are associated with increased risk for acute alcohol-withdrawal convulsions (Alcw1–3, see Table 1). Together, these three QTLs account for 68% of the genetic variability in acute alcohol-withdrawal severity among B6- and

Alcohol drinking

McClearn and Rodgers first characterized B6 mice as extreme alcohol ‘preferrers’ and D2 mice as extreme alcohol ‘avoiders’²⁸. In 1994 and 1995, two groups reported provisional mapping of several QTLs for alcohol preference drinking in BXD RI mice14, 29. Four have been confirmed, on chromosomes 1, 2, 4 and 9 (14, 15, 16, 17, 18), and a QTL for the related trait, alcohol acceptance, has been mapped to chromosome 15 (Ref. 19). Marker-based selection was used to verify the acceptance QTL (Ref. 19).

Other drug response QTLs

Standard methods were used to map 5 QTLs (Lore1–5; 21, 32) in mice selected for long (LS) or short (SS) ethanol-induced loss of the righting reflex. Marker-based selection was then used for further verification of these QTLs (Ref. 33). QTLs have also been mapped for cocaine-induced seizures (H.L. Hain, J.C. Crabbe, C.M. Merrill, S.E. Bergeson and J.K. Belknap, unpublished observations). Location of these QTLs is indicated in Fig. 1.

Significant QTLs for morphine preference drinking have been

Methodological advances to increase QTL map resolution

When a QTL is first mapped, the resolution of its location is typically coarse, that is, within 10–30 cM (see Table 1). Darvasi has recently described several options for attaining 1 cM map resolution in the mouse³⁷. These approaches include the use of advanced intercross lines, interval-specific congenic strains and recombinant inbred-segregation tests. While detailed discussion of these methods is beyond the scope of this review, the attainment of finer map resolution is important because it

Knockout approaches

The recent development of gene-targeted mutant mice that lack, underexpress or overexpress specific genes offers an excellent opportunity to evaluate the roles of their gene products in a variety of behaviors. For example, Saudou et al. produced a mouse that completely lacked 5-HT1B receptors⁴⁰. Because Htr1b was a candidate near a QTL affecting alcohol preference drinking, we tested the 5-HT_1B knockout and wild-type controls for alcohol preference. The knockout mice consumed about twice as

Future directions – more complex solutions for complex traits

QTLs detected through mapping approaches could be based on allelic differences that ultimately lead to different gene products for functional genes, that is, those with direct biological function. In such cases, pursuit of candidate functional genes will be beneficial. Alternatively, the QTL could reflect regulatory sequences or the activity of a modifier gene, which itself affects expression of other functional genes. In this case, identification of unknown genes on the basis of their

Pharmacogenetics – past and future

Rapid progress has been made in the past few years towards identifying specific genes that lead to risk of abuse or protection from the abuse of drugs. Drug responses remain a good paradigm for mapping genes for complex behavioral traits, for at least two reasons. First, there is generally a great deal of heritable genetic variance that underlies individual differences in sensitivity to drugs. It is likely that such genetic variability exists because natural selection has not opposed it, for

Acknowledgements

The authors thank Dr Steve Mitchell for Fig. 1 and Dr Kaitlin Browman for her helpful comments on a draft of this manuscript. The authors' research is supported by three grants from the US Department of Veterans Affairs, and by USPHS Grants AA11322, AA11114, AA10760, AA07468, AA06243, DA10913, DA07262 and DA05228.

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Trends in Neurosciences

ReviewIdentifying genes for alcohol and drug sensitivity: recent progress and future directions

Abstract

Section snippets

Mapping methods

Acute alcohol- and pentobarbitol-withdrawal convulsions

Alcohol drinking

Other drug response QTLs

Methodological advances to increase QTL map resolution

Knockout approaches

Future directions – more complex solutions for complex traits

Pharmacogenetics – past and future

Acknowledgements

Nature

J. Neurosci.

Drugs and the Inheritance of Behavior

Behav. Genet.

Trends Pharmacol. Sci.

Science

Nat. Genet.

Behav. Genet.

Mamm. Genome

J. Neurosci.

Alcoholism: Clin. Exp. Res.

Mamm. Genome

Alcoholism: Clin. Exp. Res.

Behav. Genet.

Nat. Genet.

Alcoholism: Clin. Exp. Res.

Mol. Psychiat.

Alcoholism: Clin. Exper. Res.

Genome Res.

Nat. Genet.

Neurobehav. Toxicol. Teratol.

Review
Identifying genes for alcohol and drug sensitivity: recent progress and future directions