Lotrich and Pollock Table 1 Strategies for selecting candidate genes for antidepressant response Enzymes and transporters affecting pharmacokinetics and disposition Potential mechanism of antidepressant action (proximally and downstream) Candidate genes for major depression and mood disorders Candidate loci from linkage studies in animal models Expression studies (mRNA and protein) to identify antidepressant- related genes Confirm preliminarily identified candidate genes individual studies will not be provided, but attention will be given to highlighting the range of potential candidate genes that can be culled using this strategy. Linkage analysis in humans to identify the genetic loci that affect treatment response has been impractical. Consequently, association analyses are essential (Tabor et al 2002). Linkage analysis does not require preselection of candidate genes, but it does require examining several sets of patients and family members who are treated similarly for depression and who are assessed using similar outcome measures (Kopnisky et al 2002; van den Bree and Owen 2003): something that is exceedingly rare. Population-based association analyses test for associa- tions of causal candidate polymorphisms or candidate polymorphisms that are tightly linked to a casual poly- morphism. Subjects do not need to be genetically related. However, given that there may be over 30 000 genes and several million polymorphisms in humans (Sachidanandam et al 2001; Venter et al 2001; Botstein and Risch 2003), densely screening the genome may require testing up to a million polymorphisms per individual (Botstein and Risch 2003). Thus, rather than screen the genome, it is currently more feasible to select a set of specific candidate genes for study. Many of these genes may interact in complex ways to affect treatment response: synergistically, antagonistically, and additively (Murphy et al 2003). Therefore, a targeted Table 2 Candidate loci with preliminary evidence for involvement in affective disorders based on association analyses Candidate polymorphisms Chromosome allocation Promoter variable repeata A218Cb Promoter variable repeatb C677T C(–1019)G C861G A(–161)T G(–1438)A C102Tb C(–759)T C178T C267T T131C C825Tb Trinucleotide repeat A758G C29Tb T1273C G1047A Promoter variable repeat Promoter variable repeat G145A G1165C C(–1291)G G158A –141C insertion/deletion A1890T C3937Tb C4075Tb 17q11.1-q12 11p15.3-p14 Xp11.4-911.3 1p36.3 5q11.2-q13 6q13 13q14-q21 Xq24 11q23.1 1p36-p35 20q13.2-q13.3 12p13 1p36.13 11p13 12q24.2-q24.31 8q13 7p15.1 5p15.3 16q12.2 10q24-q26 10q24.q26 22q11.21-q11.23 11q23 7q31-q35 19q13.2 Gene SLC6A4 TPH1 MAOA MTHFR HTR1A HTR1B HTR2A HTR2C HTR3A HTR6 GNAS1 GNB3 PLA2 BDNF NOS1 CRH CRHR2 SLC6A3 SLC6A2 ADRB1 ADRA2A COMT DRD2 CHRM2 APOE 18 General function 5-HT reuptake 5-HT synthesis 5-HT catabolism Monoamine synthesis 5-HT receptor 5-HT receptor 5-HT receptor 5-HT receptor 5-HT receptor 5-HT receptor G-protein subunit – alpha G-protein subunit – beta Phospholipase A2 Neuronal growth factor Neuronal nitric oxide synthesis Corticotropin-releasing hormone CRH receptor Dopamine transporter Norepinephrine transporter Norepinephrine beta 1 receptor Norepinephrine alpha 2 receptor Monoamine metabolism Dopamine 2 receptor Muscarinic 2 receptor Apolipoprotein E a Multiple studies replicate an association with SSRI treatment response. b Polymorphism has a potential preliminary association with antidepressant treatment response in previous studies. See text for citations. Gene nomenclature is according to HGNC (www.gene.ucl.ac.uk/nomenclature). Neuropsychiatric Disease and Treatment 2005:1(1)