Neuropsychopharmacology - Association of Multiple DRD2 Polymorphisms with Anorexia Nervosa
Anorexia nervosa (AN), a disorder with typically an adolescent age of onset, is characterized by pathologic eating behavior, by the relentless pursuit of thinness leading to emaciation, and by a mortality rate substantially greater than other psychiatric disorders (Sullivan, 1995). AN patients often display characteristic temperament and personality traits that include obsessionality, perfectionism, and anxiety (Halmi et al, 2000; Bulik et al, 2003; Kaye et al, 2004). AN is familial, with a relative risk of 11 and an additive genetic component of 60% (Strober et al, 2000; Lilenfeld et al, 1998; Wade et al, 2000; Klump et al, 2001; Kortegaard et al, 2001).
Based on this evidence for genetic susceptibility, a multi-center collaborative group, the Price Foundation Collaborative Group (PFCG), has collected a large sample of eating disorder families (N=196) ascertained from AN probands, known as the AN affected relative pair (AN-ARP) data set (Kaye et al, 2000). Using these families, the PFCG has reported suggestive linkage to chromosome 1p34–36 for restricting AN (Grice et al, 2002), as well as to 1q, 2q, and 13p (Devlin et al, 2002). In addition to linkage studies, the PFCG has investigated candidate susceptibility genes, such as those influencing monoamine and neuropeptide function (Bergen et al, 2003b). For example, we have analyzed HTR1D, OPRD1, and HCRTR1, all biological candidate genes found in the chr1p34–36 linkage region (Bergen et al, 2003a), and have identified significant case : control and TDT association to AN diagnosis at HTR1D and OPRD1 (Bergen et al, 2003a).
Disturbances of CNS dopamine metabolism could contribute to symptoms in AN. Dopaminergic neuronal function modulates feeding behavior (Szczypka et al, 1999, 2000), motor activity (Kalivas, 1993), and reward-motivated (Blum et al, 1995; Salamone, 1996) and drug-seeking behavior (Bardo et al, 1996). Aside from their well-know disturbances of feeding and weight maintenance, individuals with AN have stereotypic and hyperactive motor behavior (Kron et al, 1978; Beumont et al, 1994), anhedonic, obsessional personalities, and reduced novelty seeking (Sohlberg and Strober, 1994). Moreover, we have shown that individuals who have recovered from AN exhibit significantly lower CSF homovanillic acid concentrations than individuals with a history of BN diagnosis or control individuals (Kaye et al, 1999).
It is plausible that D2 receptors, which are most prominent in the striatum, nucleus accumbens, and olfactory tubercle (Mukherjee et al, 1996), could play a role in AN. In addition to their potential effects on feeding behavior, the striatal dopamine system affects hyperactivity, and dopamine neurons in the nucleus accumbens/limbic regions are involved in reward alterations and novelty seeking (Wise and Bozarth, 1984; Comings and Blum, 2000). The dopamine receptor D2 is a seven transmembrane G protein linked receptor that binds dopamine and inhibits adenylate cyclase (Kebabian and Calne, 1979). The literature suggests this receptor acts as an autoreceptor on dopaminergic cell bodies and as a postsynaptic receptor on dopaminergic targets (Khan et al, 1998; Usiello et al, 2000). Extending over 65 kb on chromosome 11q23, with an intron of approximately 50 kb separating exons one and two, DRD2 has been investigated as a candidate biological susceptibility locus in linkage and association studies in many psychiatric diseases (Cravchik and Goldman, 2000). Functional polymorphisms at DRD2 include the -141 Indel polymorphism, shown to affect DRD2 transcription efficiency (Arinami et al, 1997), the exon 7 nonsynonymous nucleotide polymorphism (SNP), 932C>G (Itokawa et al, 1993), shown to impair dopamine-mediated inhibition of forskolin-induced adenylate cyclase activity (Cravchik et al, 1996) and the exon 7 synonymous SNP, 957C>T (Cargill et al, 1999), shown to affect DRD2 transcript stability and translational efficiency (Duan et al, 2003). As DRD2 is a plausible candidate gene for AN, we genotyped seven SNPs that physically span the gene in both case : control and family samples and evaluated association to AN phenotype.
Anorexia nervosa (AN), a disorder with typically an adolescent age of onset, is characterized by pathologic eating behavior, by the relentless pursuit of thinness leading to emaciation, and by a mortality rate substantially greater than other psychiatric disorders (Sullivan, 1995). AN patients often display characteristic temperament and personality traits that include obsessionality, perfectionism, and anxiety (Halmi et al, 2000; Bulik et al, 2003; Kaye et al, 2004). AN is familial, with a relative risk of 11 and an additive genetic component of 60% (Strober et al, 2000; Lilenfeld et al, 1998; Wade et al, 2000; Klump et al, 2001; Kortegaard et al, 2001).
Based on this evidence for genetic susceptibility, a multi-center collaborative group, the Price Foundation Collaborative Group (PFCG), has collected a large sample of eating disorder families (N=196) ascertained from AN probands, known as the AN affected relative pair (AN-ARP) data set (Kaye et al, 2000). Using these families, the PFCG has reported suggestive linkage to chromosome 1p34–36 for restricting AN (Grice et al, 2002), as well as to 1q, 2q, and 13p (Devlin et al, 2002). In addition to linkage studies, the PFCG has investigated candidate susceptibility genes, such as those influencing monoamine and neuropeptide function (Bergen et al, 2003b). For example, we have analyzed HTR1D, OPRD1, and HCRTR1, all biological candidate genes found in the chr1p34–36 linkage region (Bergen et al, 2003a), and have identified significant case : control and TDT association to AN diagnosis at HTR1D and OPRD1 (Bergen et al, 2003a).
Disturbances of CNS dopamine metabolism could contribute to symptoms in AN. Dopaminergic neuronal function modulates feeding behavior (Szczypka et al, 1999, 2000), motor activity (Kalivas, 1993), and reward-motivated (Blum et al, 1995; Salamone, 1996) and drug-seeking behavior (Bardo et al, 1996). Aside from their well-know disturbances of feeding and weight maintenance, individuals with AN have stereotypic and hyperactive motor behavior (Kron et al, 1978; Beumont et al, 1994), anhedonic, obsessional personalities, and reduced novelty seeking (Sohlberg and Strober, 1994). Moreover, we have shown that individuals who have recovered from AN exhibit significantly lower CSF homovanillic acid concentrations than individuals with a history of BN diagnosis or control individuals (Kaye et al, 1999).
It is plausible that D2 receptors, which are most prominent in the striatum, nucleus accumbens, and olfactory tubercle (Mukherjee et al, 1996), could play a role in AN. In addition to their potential effects on feeding behavior, the striatal dopamine system affects hyperactivity, and dopamine neurons in the nucleus accumbens/limbic regions are involved in reward alterations and novelty seeking (Wise and Bozarth, 1984; Comings and Blum, 2000). The dopamine receptor D2 is a seven transmembrane G protein linked receptor that binds dopamine and inhibits adenylate cyclase (Kebabian and Calne, 1979). The literature suggests this receptor acts as an autoreceptor on dopaminergic cell bodies and as a postsynaptic receptor on dopaminergic targets (Khan et al, 1998; Usiello et al, 2000). Extending over 65 kb on chromosome 11q23, with an intron of approximately 50 kb separating exons one and two, DRD2 has been investigated as a candidate biological susceptibility locus in linkage and association studies in many psychiatric diseases (Cravchik and Goldman, 2000). Functional polymorphisms at DRD2 include the -141 Indel polymorphism, shown to affect DRD2 transcription efficiency (Arinami et al, 1997), the exon 7 nonsynonymous nucleotide polymorphism (SNP), 932C>G (Itokawa et al, 1993), shown to impair dopamine-mediated inhibition of forskolin-induced adenylate cyclase activity (Cravchik et al, 1996) and the exon 7 synonymous SNP, 957C>T (Cargill et al, 1999), shown to affect DRD2 transcript stability and translational efficiency (Duan et al, 2003). As DRD2 is a plausible candidate gene for AN, we genotyped seven SNPs that physically span the gene in both case : control and family samples and evaluated association to AN phenotype.
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