A 3p26-3p25 Genetic Linkage Finding for DSM-IV Major Depression in Heavy Smoking Families
Publication: American Journal of Psychiatry
Abstract
Objective:
The authors tested for genetic linkage of DSM-IV-diagnosed major depressive disorder in families that were ascertained for cigarette smoking.
Method:
Within a study that targeted families characterized by a history of smoking, analyses derived a subset of 91 Australian families with two or more offspring with a history of DSM-IV major depressive disorder (affected sibling pairs, N=187) and 25 Finnish families (affected sibling pairs, N=33). Within this affected sibling pairs design, the authors conducted nonparametric linkage analysis.
Results:
In the Australian heavy smoking families, the authors found a genome-wide significant multipoint LOD score of 4.14 for major depressive disorder on chromosome 3 at 24.9 cM (3p26-3p25).
Conclusions:
Genome-wide significant linkage was detected for major depressive disorder on chromosome 3p in a sample ascertained for smoking. A linkage peak at this location was also observed in an independent study of major depressive disorder.
Genetic linkage studies of major depressive disorder have found suggestive evidence across multiple genomic regions but with little convergence of findings (1). Genetic association findings, including those from genome-wide association studies (GWASs), have been similarly disparate (2–7). These inconsistencies raise the question of whether major depressive disorder encompasses a number of poorly understood subtypes (e.g., depression in smokers). Among cigarette smokers seeking cessation treatment, lifetime rates of major depression have been estimated at over 60% (8). Cigarette smokers with a history of depression tend to report more severe nicotine withdrawal symptoms (9–11), are more likely to relapse to smoking after an attempt to quit (8), and may be at increased risk for a recurrent episode of depression after smoking cessation (12). Models describing the relationship between symptoms of depression and cigarette smoking include examples of shared genetic risk (13). We carried out genetic linkage analyses of DSM-IV-diagnosed major depressive disorder in two samples that are part of the Nicotine Addiction Genetics project (14, 15), an international consortium focused on tobacco dependence. We used an affected sibling-pair design, in which at least two adult offspring per family reported a history of DSM-IV major depressive disorder, and tested for linkage. Results appear to confirm a genome-wide significant linkage signal at chromosome 3p26-3p25, also reported in an independent linkage study of major depressive disorder conducted by Breen et al. (16).
Method
Samples
The Nicotine Addiction Genetics linkage project enrolled participants at the Queensland Institute of Medical Research in Australia and the University of Helsinki in Finland. Both sites utilized twin registries and targeted families of index cases with a previously reported history of cigarette smoking in interview or questionnaire surveys; the Australian site used a higher threshold measure when recruiting index cases with a history of heavy smoking (14). These original linkage samples included microsatellite marker data and telephone diagnostic interviews for 289 families from the Australian site (offspring, N=917; parents, N=392) and 161 families from the Finnish site (offspring, N=522; parents, N=19). More than 90% of the participants from the Australian site were of Anglo-Celtic or Northern European ancestry, and all of the participants from the Finnish site were of Finnish ancestry. The assessment included a diagnostic telephone interview, adapted from the Semi-Structured Assessment for the Genetics of Alcoholism (17, 18), which obtained a comprehensive evaluation of lifetime DSM-IV (19) major depressive disorder as well as a tobacco use and dependence assessment derived from the Composite International Diagnostic Interview (20). Additional details on the original samples and assessments have been described elsewhere (14, 15, 21). For the present study, we conducted genetic linkage analyses using the 91 Australian families who had one or more affected sibling pairs concordant for a history of major depressive disorder (N=187). In the Finnish sample, only 25 families had one or more affected sibling pairs (N=33), and thus the primary analyses focused on the Australian sample. A summary of the two major depressive disorder linkage samples is presented in Table 1 of the data supplement accompanying the online version of this article.
Analyses
For both the Australian and Finnish samples, 381 autosomal microsatellite markers were genotyped and spaced at approximately 10 cM across the genome, positioned using the deCODE Genetics (Reykjavik, Iceland) map (22). Details of genotyping, including quality control procedures, are described elsewhere (14, 15). Single- and multipoint affected sibling pair nonparametric linkage (the latter using a 2-cM grid) was conducted in MERLIN (Multipoint Engine for Rapid Likelihood Inference [23]), which generated LOD scores (24, 25). Upon detection of LOD scores >3, genome-wide corrected p values were calculated from 1,000 replicates simulated in MERLIN (26, 27).
Follow-up fine mapping included the addition of 290 single nucleotide polymorphisms (SNPs) on chromosome 3 that were available for a portion of the Australian major depressive disorder linkage sample (84 out of 91 families), from other Australian projects with overlapping samples that obtained GWAS data (see reference 28). Through the use of Snagger software (29), these SNPs were selected to be in low linkage disequilibrium (maximum pairwise r2=0.2), to have a minor allele frequency >40%, and to have a minimum distance between two tags of 450 kb in order to optimize information content.
Results
For the Australian linkage sample, a multipoint LOD score of 4.14 for major depressive disorder was found on chromosome 3 (at 24.9 cM). The highest single-point linkage signal emerged at microsatellite marker D3S1304, with a LOD score of 3.7. The LOD score of 4.14 at 3p in this sample met genome-wide significance (p=0.004). A complete report of these single- and multipoint findings, along with marker positions by chromosome, is provided in Table 2 of the data supplement. The addition of 290 SNPs on chromosome 3 narrowed the linkage locus and increased the LOD score to 4.55 (at 25.3 cM) (Figure 1). For the Finnish major depressive disorder sample, a multipoint LOD score of 2.10 was found on chromosome 20 (at 90.9 cM).
FIGURE 1. Findings Observed on Chromosome 3 in an Australian Major Depressive Disorder Linkage Samplea
a The sample is taken from the Nicotine Addiction Genetics linkage project. The LOD score of 4.14 meets genome-wide significance (p=0.004), with 1,000 simulations in MERLIN.
Given that no linkage signals greater than 1.5 overlapped across both samples, we did not conduct a combined analysis. However, if we were to correct conservatively for testing in both samples by doubling the p value generated from the 1,000 simulations, we would still maintain a genome-wide significant p value of 0.008.
Discussion
Overall, major depressive disorder was associated with a significant genetic linkage peak (a LOD score of 4.14) on chromosome 3 in the Nicotine Addiction Genetics Australian sample, replicating the linkage reported at the same location by Breen et al. (16). These converging findings suggest that the genomic region spanning across 3p26-3p25 is an important area for further investigation in genetic research on major depressive disorder. Given the small number of Finnish affected sibling pairs, the lack of confirmation in this particular sample is not unexpected. The genetic variants accounting for this linkage signal have not yet been convincingly identified. Although our highest single-point microsatellite marker (D3S1304 [LOD score=3.7]) lies within the metabotropic glutamate receptor 7 gene (GRM7), subsidiary association analyses within a one-LOD support interval, using GWAS data available in the Australian sample (28), found only nominal association for two SNPs within GRM7 (p<0.05). Even our strongest association effect, which was a p value of 0.00014 for rs6765537 (a nonsynonymous SNP within C3or20 at 33.87 cM), did not replicate in the Finnish families, nor did it replicate in the Genetic Association Information Network major depressive disorder sample from the Netherlands (2, 30). Thus, while others have found suggestive association between SNPs in GRM7 and major depressive disorder (7, 31), genome-wide significant effects have not been reported. Further, because linkage implicates very broad regions, GRM7 is among many genes that might be hypothesized to explain our signal.
In terms of other linkage findings, one for quantity smoked in samples ascertained for depression has been reported near our chromosome 3 finding for major depressive disorder (32), raising the possibility of common genetic influences across major depressive disorder and smoking-related behavior or of gene-by-environment (i.e., smoking) interaction effects on major depressive disorder.
There are important limitations associated with our results. Our sample of 91 families is small by standards of modern genomic efforts. Thus, we cannot exclude the possibility that our finding is a false positive that coincidentally appears to replicate that of Breen et al. (16), whose sample is much larger (>800 families). Additionally, our finding at 3p26-3p25 (highest peak at 24.9 cM) does not align with the meta-analyses results reported by McMahon et al. (33), who suggest that variants located at 3p21.1 (at approximately 70–72 cM) are associated with mood disorders. Our future efforts to localize the genetic variants influencing major depressive disorder will entail confirmatory analyses in other samples and additional genotyping in this region on chromosome 3p.
Acknowledgments
The authors acknowledge the important roles of Drs. Richard Todd and Leena Peltonen, two recently deceased senior investigators, for their contributions to the present project and, more broadly, to the field of psychiatric genetics.
The authors also thank the Australian and Finnish families for their participation and cooperation as well as the staff from all three Nicotine Addiction Genetics project sites.
Footnotes
Received Sept. 17, 2010; revisions received Dec. 21, 2010 and Feb. 22, 2011; accepted Feb. 28, 2011.
The Nicotine Addiction Genetics project is an international collaborative study that includes the following three sites: Queensland Institute of Medical Research, Queensland, Australia (principal investigator, Dr. Martin); the University of Helsinki, Helsinki (principal investigator, Dr. Kaprio); and Washington University, St. Louis (principal investigator, Dr. Madden). Data collection is conducted at the Queensland Institute of Medical Research and the University of Helsinki, with Washington University serving as the coordinating site and lead institution. Genotyping and data analysis are conducted at all three sites.
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Information & Authors
Information
Published In
History
Received: 17 September 2010
Revision received: 21 December 2010
Revision received: 22 February 2011
Accepted: 28 February 2011
Published online: 1 August 2011
Published in print: August 2011
Authors
Funding Information
Dr. Pergadia receives funding from a K08 award (grant DA019951) from the National Institute on Drug Abuse. Dr. Glowinski is the principal investigator for the National Institutes of Health grant MH-073151 and a co-investigator of grants AA015210 and R49CE001510; she also serves on the advisory board for the Klingenstein Third Generation Foundation. Dr. Wray has received speaker's honorarium from Eli Lilly; she also receives funding from an Australian Research Council Future Fellowship. Dr. Agrawal receives funding from the National Institutes of Health and has served as a principal investigator for the Alcoholic Beverage Medical Research Foundation/The Foundation for Alcohol Research. Dr. Saccone receives funding from the National Institutes of Health (grant DA024722). Dr. Loukola receives funding from an Academy of Finland postdoctoral fellowship. Dr. Broms has received funding from the Doctoral Programs of Public Health, University of Helsinki; and she has received a consultation fee from Pfizer (for nicotine dependence measurements). Dr. Grant receives funding from the National Institutes of Health. Dr. Nelson has received research support from the National Institutes of Health and the U.S. Department of Defense. Ms. Chou receives salary funding through a National Institutes of Health grant. Dr. Vink receives funding from the Netherlands Organisation for Scientific Research (VENI grant 451–06-004). Dr. MacGregor receives funding from an Australian National Health and Medical Research Council fellowship. Mr. Liu receives funding from the Australian National Health and Medical Research Council (project grant 496675). Dr. Medland receives funding from a National Health and Medical Research Council (Australia) Sidney Sax Fellowship. Dr. Montgomery receives funding from an Australian National Health and Medical Research Council fellowship. Dr. Goate has received research funding and speaker's honoraria from AstraZeneca, Genentech, and Pfizer; she has also received advisory panel payment from AstraZeneca. Dr. Heath has received funding from the National Institutes of Health (grants AA07728, AA07580, AA11998, AA13320, AA13321, and AA017688). Dr. Kaprio has received a consultation fee from Pfizer (for pharmacogenetics for smoking cessation) as well as an unrestricted grant from Pfizer for the Global Research Awards for Nicotine Dependence; he has also received funding from the Academy of Finland Center of Excellence for Complex Disease Genetics. Dr. Madden is principal investigator for the National Institutes of Health grants DA12854 and DA027995; she is also coinvestigator for grants AA011998, AA017915, DA018267, and DA23668. All other authors report no financial relationships with commercial interests.Supported by a Center for Inherited Disease Research grant to fund genome-wide association studies (to the late Dr. Richard Todd, former principal investigator of grant AA13320) and the European Union (contract number QLG2-CT-2002-01254 [Dr. Kaprio]).Funding for the Genetic Association Information Network (GAIN) major depressive disorder study (parent studies were the Netherlands Study of Depression and Anxiety and the Netherlands Twin Register) was provided by the Netherlands Scientific Organization (grants 904–61-090, 904–61-193, 480–04-004, 400–05-717, and 911–09-032); the Netherlands Organisation for Scientific Research Genomics program (grant SPI-56–464-14192); the Centre for Neurogenomics and Cognitive Research; the Genetics of Mental Illness (grant ERC-230374); the European Union (grant EU/WLRT-2001–01254); ZonMW (geestkracht program grant 10–000-1002); the National Institute of Mental Health (grant RO1 MH-059160); and matching funds from participating institutes of the Netherlands Study of Depression and Anxiety and the Netherlands Twin Register. The genotyping of GAIN samples was provided through grant MH-081802. The data set can be found online at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000020.v2.p1.
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