Letters to the Editor 707 SADS-LB) and diagnoses met DSM-IV criteria. Asso- References ciation analyses were performed using the TDT,4 ETDT5 and Transmit6 programmes. 1 Tosato S, Dazzan P, Collier D. Association between the neuregulin 1 gene and schizophrenia: a systematic review. Schizophr Bull From the single marker association analysis, there 2005; 31: 613–617. was no evidence of association of NRG1 with BPAD in 2 Maier W, Hofgen B, Zobel A, Rietschel M. Genetic models our sample (Table 1). D8S1810 did exhibit a signi- of schizophrenia and bipolar disorder: overlapping inheritance ficant over transmission of allele 5 to bipolar probands or discrete genotypes? Eur Arch Psychiatry Clin Neurosci 2005; 255: 159–166. (uncorrected P = 0.04) but the global P-value for this 3 Green EK, Raybould R, Macgregor S, Gordon-Smith K, Heron J, marker was not significant (Table 1: P =0.212). Inter- Hyde S et al. Operation of the schizophrenia susceptibility estingly, this marker was selected based on its presence gene, neuregulin 1, across traditional diagnostic boundaries to within an Irish schizophrenia-associated haplotype, increase risk for bipolar disorder. Arch Gen Psychiatry 2005; 62: HapB .7 A range of two to three marker haplotypes, 642–648. IRE 4 Spielman RS, McGinnis RE, Ewens WJ. Transmission test for including HAPICE and HapBIRE, also failed to exhibit linkage disequilibrium: the insulin gene region and insulin- any evidence of association with BPAD (Table 1). A dependent diabetes mellitus. Am J Hum Genet 1993; 52: 506–516. haplotype comprised of alleles from the three micro- 5 Sham PC, Curtis D. An extended transmission/disequilibrium satellite markers (M3-M4-M5) did exhibit a marginal test for multi-allele marker loci. Ann Hum Genet 1995; 59(Pt3): 323–336. association (Table 1, haplotype 1, 3, 5, uncorrected 6 Clayton D. A generalization of the transmission/disequilibrium P = 0.04) which was not significant at the global test for uncertain-haplotype transmission. Am J Hum Genet 1999; haplotype level (Table 1: P = 0.31). We hypothesized 65: 1170–1177. that if NRG1 is principally a gene for schizophrenia, a 7 Corvin AP, Morris DW, McGhee K, Schwaiger S, Scully P, Quinn J stratified analysis restricted to trios with probands that et al. Confirmation and refinement of an ’at-risk’ haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential have experienced at least one psychotic episode may susceptibility gene at the Neuregulin-1 locus. Mol Psychiatry 2004; reveal an association with BPAD, similar to the 9: 208–213. findings of Green et al.3 However, restriction of the 8 Thiselton DL, Webb BT, Neale BM, Ribble RC, O’Neill FA, association analysis to the subset of 59 trios with Walsh D et al. No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high- psychosis did not reveal any evidence for association density schizophrenia families (ISHDSF). Mol Psychiatry 2004; 9: of NRG1 with BPAD (data not shown). 777–783. To conclude, we have failed to replicate the findings 9 Morris DMK, Schwaiger S, Nangle J, Murphy K, Donohoe G, of Green et al.3 in a family-based collection which is not Clarke S et al. Abstracts for the XIIth World Congress of subject to the population substructure effects of case– Psychiatric Genetics. Dublin, Ireland, 9–13 October 2004. Am J Med Genet B Neuropsychiatr Genet 2004; 130: 143 (poster control association studies. These findings suggest that 14.62). NRG1 is not a susceptibility gene for BPAD in the Irish 10 Gardner M, Gonzalez-Neira A, Lao O, Calafell F, Bertranpetit J, population. Interestingly, despite a plethora of positive Comas D. Extreme population differences across Neuregulin 1 associations of NRG1 with schizophrenia in diverse gene, with implications for association studies. Mol Psychiatry 2006; 11: 66–75. populations, the two Irish schizophrenia investigations have also been negative.8,9 Although a two-marker NRG1 haplotype (HapBIRE) was initially reported to be associated with schizophrenia in an Irish case–control sample,7 the association was no longer evident after Serotonin transporter further investigation within an extended sample.9 We cannot rule out the possibility that our collection had polymorphism and insufficient power to replicate the association of NRG1 with BPAD. Indeed, there are moderate differences in LDL-cholesterol the allele frequencies for SNPs surrounding the core haplotype in European populations, which would impact the power of replication studies, particularly Molecular Psychiatry (2006) 11, 707–709. for rarer alleles/haplotypes.10 However, geographical doi:10.1038/sj.mp.4001837 variationisunlikelytobeanissueinthiscaseasthe estimated frequency of the core haplotype in our samples (7.7%) was very similar to that reported by The short allele of the serotonin transporter poly- Green et al.3 (7.8% in controls). To elucidate whether morphism (5HTTLPR) has been linked to psychiatric NRG1 is truly a susceptibility gene for BPAD, addi- disorders, including depression or anxiety. Our tional studies in family-based collections are required. analyses concerning the impact of 5HTTLPR on late- onset depression in a large community-based age- F Cassidy1, S Roche1, E Claffey2 and P McKeon2,3 cohort unexpectedly detected that 5HTTLPR strongly 1Smurfit Institute of Genetics, Trinity College, influences low-density lipoprotein (LDL)-cholesterol Dublin, Ireland; 2Depression Research Unit, levels. St Patrick’s Hospital, Dublin, Ireland and The serotonin transporter (SERT) regulates the 3Department of Psychiatry, Trinity College, serotonergic system via modulation of extracellular Dublin, Ireland. fluid serotonin concentrations. Transcriptional acti- E-mail: [email protected] vity of human SERT is modulated by a repetitive Molecular Psychiatry Letters to the Editor 708 Table 1 Demographic data in different 5HTTLPR genotypes; unless otherwise indicated, data are means7s.d. SS SL LL n (LDL-cholesterol measured) 92 (91) 270 (267) 204 (203) Female/male 53/39 160/110 120/84 LDL-cholesterol (mg/dl)a 137737 145739 154743 HDL-cholesterol (mg/dl) 59715 59716 58714 Triglycerides (mg/dl) 125761 136777 138767 Systolic blood pressure (mm Hg) 147720 147720 147721 Diastolic blood pressure (mm Hg) 84710 82711 81710 Body mass index 277427742774 HbA1c (five of total haemoglobin) 5.871.1 6.073.5 5.870.9 History of smoking, yes/no 44/48 112/158 90/114 Myocardial infarction or stroke, yes/no 12/80 36/234 37/167 On lipid-lowering drugs yes/no 16/76 61/209 42/162 Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein. aANOVA, df = 558, F = 6.44, P = 0.002; level of significance P = 0.006 (Bonferroni corrected). element of varying length, in the 50 flanking region LPR in women (43 women with SS: 147 (37); 119 located B1.4 kb from the transcription start site, women with SL: 153 (33); 97 women with LL: 170 termed the serotonin transporter gene-linked poly- (41); ANOVA, df = 256, F = 7.66, P = 0.001), but non- morphic region (5HTTLPR). 5HTTLPR alleles are significantly in men (32 men with SS: 137 (35); 87 most commonly composed of either 14 (‘short’ men with SL: 143 (44); 64 men with LL: 149 (36)). allele S) or 16 (‘long’ allele L) repeated elements. Therapy with lipid-lowering drugs, high-density The 5HTTLPR genotype distribution in a Caucasian lipoprotein-cholesterol levels, triglyceride levels, population is 32% LL, 49% LS and 19% SS.1 The blood pressure, HbA1c, history of smoking and body serotonin transporter may contribute to several dis- mass index were not associated with 5HTTLPR. A orders and most reports comprise neuropsychiatric history of myocardial infarction or stroke in indivi- phenotypes such as anxiety disorders, depression and duals not taking lipid-lowering drugs was found in bipolar disorder linked to the S allele.2 There are only 16% of individuals with LL genotype, but with a few examples of apparent SERT-related dysfunction significantly lower frequency (8.8%) in individuals in the periphery. Nevertheless, serotonin plays an carrying the S allele (Fisher’s exact test: P = 0.029). important role outside the central nervous system, Data from this epidemiological study replicated the particularly in sustaining gastrointestinal function.3 finding of an association between artherosclerosis Two studies found significantly greater risk for events and the LL genotype of 5HTTLPR. Our myocardial infarction in individuals with the LL analyses further detected that 5HTTLPR influences genotype.4,5 The latter findings remain unexplained. LDL-cholesterol levels, especially in women. The The Vienna Transdanube Aging (VITA) study L-allele was associated with higher LDL-cholesterol, investigates an age cohort (mean age 75.7 years, and the S-allele with lower LDL-cholesterol. In case s.d. = 0.45 years) of all inhabitants of a defined of replication, this finding will induce a great deal geographical area in Vienna, Austria.6 Six hundred of research on the serotonergic influence on and ninety-seven out of 1505 inhabitants of this LDL-cholesterol. age participated; blood could be investigated in 606 participants and 5HTTLPR could be examined in 566 P Fischer1, E Gruenblatt2, P Pietschmann3 individuals (Table 1). and K-H Tragl4 The 5HTTLPR genotype distribution in the VITA 1Department of General Psychiatry, Medical population is 36% LL, 48% SL and 16% SS, which University of Vienna and Ludwig Boltzmann Institute does not deviate from Hardy–Weinberg equilibrium of Aging Research, Vienna, Austria; 2Institute of (w2 = 0.0281, P