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New Research   |    
A 3p26-3p25 Genetic Linkage Finding for DSM-IV Major Depression in Heavy Smoking Families
Michele L. Pergadia, Ph.D.; Anne L. Glowinski, M.D., M.P.E.; Naomi R. Wray, Ph.D.; Arpana Agrawal, Ph.D.; Scott F. Saccone, Ph.D.; Anu Loukola, Ph.D.; Ulla Broms, Ph.D.; Tellervo Korhonen, Ph.D.; Brenda W.J.H. Penninx, Ph.D.; Julia D. Grant, Ph.D.; Elliot C. Nelson, M.D.; Anjali K. Henders, B.Sc. (Hons.); Andrew J. Schrage, M.S.; Yi-Ling Chou, M.S.; Kaisu Keskitalo-Vuokko, Ph.D.; Qin Zhu, M.S.; Scott D. Gordon, Ph.D.; Jacqueline M. Vink, Ph.D.; Eco J.C. de Geus, Ph.D.; Stuart MacGregor, Ph.D.; Jimmy Z. Liu, B.Sc. (Hons.); Gonneke Willemsen, Ph.D.; Sarah E. Medland, Ph.D.; Dorret I. Boomsma, Ph.D.; Grant W. Montgomery, Ph.D.; John P. Rice, Ph.D.; Alison M. Goate, D.Phil.; Andrew C. Heath, D.Phil.; Jaakko Kaprio, M.D., Ph.D.; Nicholas G. Martin, Ph.D.; Pamela A.F. Madden, Ph.D.
Am J Psychiatry 2011;168:848-852. doi:10.1176/appi.ajp.2011.10091319
View Author and Article Information
From the Department of Psychiatry, Washington University School of Medicine, Saint Louis; the Department of Genetics, Washington University School of Medicine, St. Louis; the Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki; the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki; the Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki; the Queensland Institute of Medical Research, Brisbane, Australia; the Department of Mental Health and Substance Abuse Services, National Institute of Health and Welfare, Helsinki; the Department of Psychiatry and EMGO Institute for Health and Care Research, Vrije Universiteit University Medical Center, Amsterdam; and the Department of Biological Psychology, Vrije Universiteit University Amsterdam, Amsterdam.

Received Sept. 17, 2010; revisions received Dec. 21, 2010 and Feb. 22, 2011; accepted Feb. 28, 2011.

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.

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.

Address correspondence and reprint requests to Dr. Pergadia, Washington University School of Medicine, Department of Psychiatry, CB 8134 660 S. Euclid Ave., St. Louis, MO 63110; pergadim@psychiatry.wustl.edu (e-mail).

Received September 17, 2010; Revised December 21, 2010; Revised February 22, 2011; Accepted February 28, 2011.

Copyright © American Psychiatric Association

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.

Abstract Teaser
Figures in this Article

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 (27). 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 (911), 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).

+

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.

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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.

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).

 
Anchor for JumpAnchor for Jump
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.

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.

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.

Levinson  DF:  The genetics of depression: a review.  Biol Psychiatry 2006; 60:84—92
[CrossRef] | [PubMed]
 
Sullivan  PF;  de Geus  EJ;  Willemsen  G;  James  MR;  Smit  JH;  Zandbelt  T;  Arolt  V;  Baune  BT;  Blackwood  D;  Cichon  S;  Coventry  WL;  Domschke  K;  Farmer  A;  Fava  M;  Gordon  SD;  He  Q;  Heath  AC;  Heutink  P;  Holsboer  F;  Hoogendijk  WJ;  Hottenga  JJ;  Hu  Y;  Kohli  M;  Lin  D;  Lucae  S;  Macintyre  DJ;  Maier  W;  McGhee  KA;  McGuffin  P;  Montgomery  GW;  Muir  WJ;  Nolen  WA;  Nöthen  MM;  Perlis  RH;  Pirlo  K;  Posthuma  D;  Rietschel  M;  Rizzu  P;  Schosser  A;  Smit  AB;  Smoller  JW;  Tzeng  JY;  van Dyck  R;  Verhage  M;  Zitman  FG;  Martin  NG;  Wray  NR;  Boomsma  DI;  Penninx  BW:  Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.  Mol Psychiatry 2009; 14:359—375
[CrossRef] | [PubMed]
 
Lewis  CM;  Ng  MY;  Butler  AW;  Cohen-Woods  S;  Uher  R;  Pirlo  K;  Weale  ME;  Schosser  A;  Paredes  UM;  Rivera  M;  Craddock  N;  Owen  MJ;  Jones  L;  Jones  I;  Korszun  A;  Aitchison  KJ;  Shi  J;  Quinn  JP;  Mackenzie  A;  Vollenweider  P;  Waeber  G;  Heath  S;  Lathrop  M;  Muglia  P;  Barnes  MR;  Whittaker  JC;  Tozzi  F;  Holsboer  F;  Preisig  M;  Farmer  AE;  Breen  G;  Craig  IW;  McGuffin  P:  Genome-wide association study of major recurrent depression in the UK population.  Am J Psychiatry 2010; 167:949—957
[CrossRef] | [PubMed]
 
Bosker  FJ;  Hartman  CA;  Nolte  IM;  Prins  BP;  Terpstra  P;  Posthuma  D;  van Veen  T;  Willemsen  G;  Derijk  RH;  de Geus  EJ;  Hoogendijk  WJ;  Sullivan  PF;  Penninx  BW;  Boomsma  DI;  Snieder  H;  Nolen  WA:  Poor replication of candidate genes for major depressive disorder using genome-wide association data.  Mol Psychiatry  (Epub ahead of print,  March 30, 2010)
 
Wray  NR;  Pergadia  ML;  Blackwood  DH;  Penninx  BW;  Gordon  SD;  Nyholt  DR;  Ripke  S;  Macintyre  DJ;  McGhee  KA;  Maclean  AW;  Smit  JH;  Hottenga  JJ;  Willemsen  G;  Middeldorp  CM;  de Geus  EJ;  Lewis  CM;  McGuffin  P;  Hickie  IB;  van den Oord  EJ;  Liu  JZ;  Macgregor  S;  McEvoy  BP;  Byrne  EM;  Medland  SE;  Statham  DJ;  Henders  AK;  Heath  AC;  Montgomery  GW;  Martin  NG;  Boomsma  DI;  Madden  PA;  Sullivan  PF:  Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned.  Mol Psychiatry  (Epub ahead of print,  November 2, 2010)
 
Shi  J;  Potash  JB;  Knowles  JA;  Weissman  MM;  Coryell  W;  Scheftner  WA;  Lawson  WB;  DePaulo  JR  Jr;  Gejman  PV;  Sanders  AR;  Johnson  JK;  Adams  P;  Chaudhury  S;  Jancic  D;  Evgrafov  O;  Zvinyatskovskiy  A;  Ertman  N;  Gladis  M;  Neimanas  K;  Goodell  M;  Hale  N;  Ney  N;  Verma  R;  Mirel  D;  Holmans  P;  Levinson  DF:  Genome-wide association study of recurrent early-onset major depressive disorder.  Mol Psychiatry 2011; 16:193—201
[CrossRef] | [PubMed]
 
Shyn  SI;  Shi  J;  Kraft  JB;  Potash  JB;  Knowles  JA;  Weissman  MM;  Garriock  HA;  Yokoyama  JS;  McGrath  PJ;  Peters  EJ;  Scheftner  WA;  Coryell  W;  Lawson  WB;  Jancic  D;  Gejman  PV;  Sanders  AR;  Holmans  P;  Slager  SL;  Levinson  DF;  Hamilton  SP:  Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.  Mol Psychiatry 2011; 16:202—215
[CrossRef] | [PubMed]
 
Glassman  AH;  Stetner  F;  Walsh  BT;  Raizman  PS;  Fleiss  JL;  Cooper  TB;  Covey  LS:  Heavy smokers, smoking cessation, and clonidine: results of a double-blind, randomized trial.  JAMA 1988; 259:2863—2866
[CrossRef] | [PubMed]
 
Covey  LS;  Glassman  AH;  Stetner  F:  Depression and depressive symptoms in smoking cessation.  Compr Psychiatry 1990; 31:350—354
[CrossRef] | [PubMed]
 
Madden  PA;  Bucholz  KK;  Dinwiddie  SH;  Slutske  WS;  Bierut  LJ;  Statham  DJ;  Dunne  MP;  Martin  NG;  Heath  AC:  Nicotine withdrawal in women.  Addiction 1997; 92:889—902
[CrossRef] | [PubMed]
 
Pergadia  ML;  Agrawal  A;  Heath  AC;  Martin  NG;  Bucholz  KK;  Madden  PA:  Nicotine withdrawal symptoms in adolescent and adult twins.  Twin Res Hum Genet 2010; 13:359—369
[CrossRef] | [PubMed]
 
Glassman  AH;  Covey  LS;  Stetner  F;  Rivelli  S:  Smoking cessation and the course of major depression: a follow-up study.  Lancet 2001; 357:1929—1932
[CrossRef] | [PubMed]
 
Kendler  KS;  Neale  MC;  MacLean  CJ;  Heath  AC;  Eaves  LJ;  Kessler  RC:  Smoking and major depression: a causal analysis.  Arch Gen Psychiatry 1993; 50:36—43
[PubMed]
[CrossRef]
 
Saccone  SF;  Pergadia  ML;  Loukola  A;  Broms  U;  Montgomery  GW;  Wang  JC;  Agrawal  A;  Dick  DM;  Heath  AC;  Todorov  AA;  Maunu  H;  Heikkila  K;  Morley  KI;  Rice  JP;  Todd  RD;  Kaprio  J;  Peltonen  L;  Martin  NG;  Goate  AM;  Madden  PA:  Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples.  Am J Hum Genet 2007; 80:856—866
[CrossRef] | [PubMed]
 
Loukola  A;  Broms  U;  Maunu  H;  Widén  E;  Heikkilä  K;  Siivola  M;  Salo  A;  Pergadia  ML;  Nyman  E;  Sammalisto  S;  Perola  M;  Agrawal  A;  Heath  AC;  Martin  NG;  Madden  PA;  Peltonen  L;  Kaprio  J:  Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background.  Pharmacogenomics J 2008; 8:209—219
[CrossRef] | [PubMed]
 
Breen  G;  Webb  BT;  Butler  AW;  van den Oord  EJCG;  Tozzi  F;  Craddock  N;  Gill  M;  Korszun  A;  Maier  W;  Middleton  L;  Mors  O;  Owen  MJ;  Cohen-Woods  S;  Perry  J;  Galwey  NW;  Upmanyu  R;  Craig  I;  Lewis  CM;  Ng  M;  Brewster  S;  Preisig  M;  Rietschel  M;  Jones  L;  Knight  J;  Rice  J;  Muglia  P;  Farmer  AE;  McGuffin  P:  A genome-wide significant linkage for severe depression on chromosome 3: the Depression Network Study.  Am J Psychiatry  (published online  May 16, 2011; doi:10.1176/appi.ajp.2011.10091342)
 
Bucholz  KK;  Cadoret  R;  Cloninger  CR;  Dinwiddie  SH;  Hesselbrock  VM;  Nurnberger  JI  Jr;  Reich  T;  Schmidt  I;  Schuckit  MA:  A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA.  J Stud Alcohol 1994; 55:149—158
[PubMed]
 
Hesselbrock  M;  Easton  C;  Bucholz  KK;  Schuckit  M;  Hesselbrock  V:  A validity study of the SSAGA: a comparison with the SCAN.  Addiction 1999; 94:1361—1370
[CrossRef] | [PubMed]
 
American Psychiatric Association:  Diagnostic and Statistical Manual of Mental Disorders , 4th ed (DSM-IV).  Washington, DC,  American Psychiatric Publishing, 1994
 
Cottler  LB;  Robins  LN;  Grant  BF;  Blaine  J;  Towle  LH;  Wittchen  HU;  Sartorius  N:  The CIDI-core substance abuse and dependence questions: cross-cultural and nosological issues: the WHO/ADAMHA Field Trial.  Br J Psychiatry 1991; 159:653—658
[CrossRef] | [PubMed]
 
Pergadia  ML;  Agrawal  A;  Loukola  A;  Montgomery  GW;  Broms  U;  Saccone  SF;  Wang  JC;  Todorov  AA;  Heikkilä  K;  Statham  DJ;  Henders  AK;  Campbell  MJ;  Rice  JP;  Todd  RD;  Heath  AC;  Goate  AM;  Peltonen  L;  Kaprio  J;  Martin  NG;  Madden  PA:  Genetic linkage findings for DSM-IV nicotine withdrawal in two populations.  Am J Med Genet B Neuropsychiatr Genet 2009; 150B:950—959
[CrossRef] | [PubMed]
 
Kong  A;  Gudbjartsson  DF;  Sainz  J;  Jonsdottir  GM;  Gudjonsson  SA;  Richardsson  B;  Sigurdardottir  S;  Barnard  J;  Hallbeck  B;  Masson  G;  Shlien  A;  Palsson  ST;  Frigge  ML;  Thorgeirsson  TE;  Gulcher  JR;  Stefansson  K:  A high-resolution recombination map of the human genome.  Nat Genet 2002; 31:241—247
[PubMed]
 
Abecasis  GR;  Cherny  SS;  Cookson  WO;  Cardon  LR:  MERLIN: rapid analysis of dense genetic maps using sparse gene flow trees.  Nat Genet 2002; 30:97—101
[CrossRef] | [PubMed]
 
Kong  A;  Cox  NJ:  Allele-sharing models: LOD scores and accurate linkage tests.  Am J Hum Genet 1997; 61:1179—1188
[CrossRef] | [PubMed]
 
Whittemore  AS;  Halpern  J:  A class of tests for linkage using affected pedigree members.  Biometrics 1994; 50:118—127
[CrossRef] | [PubMed]
 
North  BV;  Curtis  D;  Sham  PC:  A note on the calculation of empirical p values from Monte Carlo procedures.  Am J Hum Genet 2002; 71:439—441
[CrossRef] | [PubMed]
 
North  BV;  Curtis  D;  Sham  PC:  A note on calculation of empirical p values from Monte Carlo procedure.  Am J Hum Genet 2003; 72:498—499
[CrossRef] | [PubMed]
 
Medland  SE;  Nyholt  DR;  Painter  JN;  McEvoy  BP;  McRae  AF;  Zhu  G;  Gordon  SD;  Ferreira  MA;  Wright  MJ;  Henders  AK;  Campbell  MJ;  Duffy  DL;  Hansell  NK;  Macgregor  S;  Slutske  WS;  Heath  AC;  Montgomery  GW;  Martin  NG:  Common variants in the trichohyalin gene are associated with straight hair in Europeans.  Am J Hum Genet 2009; 85:750—755
[CrossRef] | [PubMed]
 
Edlund  CK;  Lee  WH;  Li  D;  van den Berg  DJ;  Conti  DV:  Snagger: a user-friendly program for incorporating additional information for tagSNP selection.  BMC Bioinformatics 2008; 9:174
[CrossRef] | [PubMed]
 
Boomsma  DI;  Willemsen  G;  Sullivan  PF;  Heutink  P;  Meijer  P;  Sondervan  D;  Kluft  C;  Smit  G;  Nolen  WA;  Zitman  FG;  Smit  JH;  Hoogendijk  WJ;  van Dyck  R;  de Geus  EJ;  Penninx  BW:  Genome-wide association of major depression: description of samples for the GAIN Major Depressive Disorder Study: NTR and NESDA biobank projects.  Eur J Hum Genet 2008; 16:335—342
[CrossRef] | [PubMed]
 
Muglia  P;  Tozzi  F;  Galwey  NW;  Francks  C;  Upmanyu  R;  Kong  XQ;  Antoniades  A;  Domenici  E;  Perry  J;  Rothen  S;  Vandeleur  CL;  Mooser  V;  Waeber  G;  Vollenweider  P;  Preisig  M;  Lucae  S;  Müller-Myhsok  B;  Holsboer  F;  Middleton  LT;  Roses  AD:  Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts.  Mol Psychiatry 2010; 15:589—601
[CrossRef] | [PubMed]
 
Vink  JM;  Beem  AL;  Posthuma  D;  Neale  MC;  Willemsen  G;  Kendler  KS;  Slagboom  PE;  Boomsma  DI:  Linkage analysis of smoking initiation and quantity in Dutch sibling pairs.  Pharmacogenomics J 2004; 4:274—282
[CrossRef] | [PubMed]
 
McMahon  FJ;  Akula  N;  Schulze  TG;  Muglia  P;  Tozzi  F;  Detera-Wadleigh  SD;  Steele  CJ;  Breuer  R;  Strohmaier  J;  Wendland  JR;  Mattheisen  M;  Mühleisen  TW;  Maier  W;  Nöthen  MM;  Cichon  S;  Farmer  A;  Vincent  JB;  Holsboer  F;  Preisig  M;  Rietschel  MBipolar Disorder Genome Study (BiGS) Consortium:  Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1.  Nat Genet 2010; 42:128—131
[CrossRef] | [PubMed]
 
References Container

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.

+

References

Levinson  DF:  The genetics of depression: a review.  Biol Psychiatry 2006; 60:84—92
[CrossRef] | [PubMed]
 
Sullivan  PF;  de Geus  EJ;  Willemsen  G;  James  MR;  Smit  JH;  Zandbelt  T;  Arolt  V;  Baune  BT;  Blackwood  D;  Cichon  S;  Coventry  WL;  Domschke  K;  Farmer  A;  Fava  M;  Gordon  SD;  He  Q;  Heath  AC;  Heutink  P;  Holsboer  F;  Hoogendijk  WJ;  Hottenga  JJ;  Hu  Y;  Kohli  M;  Lin  D;  Lucae  S;  Macintyre  DJ;  Maier  W;  McGhee  KA;  McGuffin  P;  Montgomery  GW;  Muir  WJ;  Nolen  WA;  Nöthen  MM;  Perlis  RH;  Pirlo  K;  Posthuma  D;  Rietschel  M;  Rizzu  P;  Schosser  A;  Smit  AB;  Smoller  JW;  Tzeng  JY;  van Dyck  R;  Verhage  M;  Zitman  FG;  Martin  NG;  Wray  NR;  Boomsma  DI;  Penninx  BW:  Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.  Mol Psychiatry 2009; 14:359—375
[CrossRef] | [PubMed]
 
Lewis  CM;  Ng  MY;  Butler  AW;  Cohen-Woods  S;  Uher  R;  Pirlo  K;  Weale  ME;  Schosser  A;  Paredes  UM;  Rivera  M;  Craddock  N;  Owen  MJ;  Jones  L;  Jones  I;  Korszun  A;  Aitchison  KJ;  Shi  J;  Quinn  JP;  Mackenzie  A;  Vollenweider  P;  Waeber  G;  Heath  S;  Lathrop  M;  Muglia  P;  Barnes  MR;  Whittaker  JC;  Tozzi  F;  Holsboer  F;  Preisig  M;  Farmer  AE;  Breen  G;  Craig  IW;  McGuffin  P:  Genome-wide association study of major recurrent depression in the UK population.  Am J Psychiatry 2010; 167:949—957
[CrossRef] | [PubMed]
 
Bosker  FJ;  Hartman  CA;  Nolte  IM;  Prins  BP;  Terpstra  P;  Posthuma  D;  van Veen  T;  Willemsen  G;  Derijk  RH;  de Geus  EJ;  Hoogendijk  WJ;  Sullivan  PF;  Penninx  BW;  Boomsma  DI;  Snieder  H;  Nolen  WA:  Poor replication of candidate genes for major depressive disorder using genome-wide association data.  Mol Psychiatry  (Epub ahead of print,  March 30, 2010)
 
Wray  NR;  Pergadia  ML;  Blackwood  DH;  Penninx  BW;  Gordon  SD;  Nyholt  DR;  Ripke  S;  Macintyre  DJ;  McGhee  KA;  Maclean  AW;  Smit  JH;  Hottenga  JJ;  Willemsen  G;  Middeldorp  CM;  de Geus  EJ;  Lewis  CM;  McGuffin  P;  Hickie  IB;  van den Oord  EJ;  Liu  JZ;  Macgregor  S;  McEvoy  BP;  Byrne  EM;  Medland  SE;  Statham  DJ;  Henders  AK;  Heath  AC;  Montgomery  GW;  Martin  NG;  Boomsma  DI;  Madden  PA;  Sullivan  PF:  Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned.  Mol Psychiatry  (Epub ahead of print,  November 2, 2010)
 
Shi  J;  Potash  JB;  Knowles  JA;  Weissman  MM;  Coryell  W;  Scheftner  WA;  Lawson  WB;  DePaulo  JR  Jr;  Gejman  PV;  Sanders  AR;  Johnson  JK;  Adams  P;  Chaudhury  S;  Jancic  D;  Evgrafov  O;  Zvinyatskovskiy  A;  Ertman  N;  Gladis  M;  Neimanas  K;  Goodell  M;  Hale  N;  Ney  N;  Verma  R;  Mirel  D;  Holmans  P;  Levinson  DF:  Genome-wide association study of recurrent early-onset major depressive disorder.  Mol Psychiatry 2011; 16:193—201
[CrossRef] | [PubMed]
 
Shyn  SI;  Shi  J;  Kraft  JB;  Potash  JB;  Knowles  JA;  Weissman  MM;  Garriock  HA;  Yokoyama  JS;  McGrath  PJ;  Peters  EJ;  Scheftner  WA;  Coryell  W;  Lawson  WB;  Jancic  D;  Gejman  PV;  Sanders  AR;  Holmans  P;  Slager  SL;  Levinson  DF;  Hamilton  SP:  Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.  Mol Psychiatry 2011; 16:202—215
[CrossRef] | [PubMed]
 
Glassman  AH;  Stetner  F;  Walsh  BT;  Raizman  PS;  Fleiss  JL;  Cooper  TB;  Covey  LS:  Heavy smokers, smoking cessation, and clonidine: results of a double-blind, randomized trial.  JAMA 1988; 259:2863—2866
[CrossRef] | [PubMed]
 
Covey  LS;  Glassman  AH;  Stetner  F:  Depression and depressive symptoms in smoking cessation.  Compr Psychiatry 1990; 31:350—354
[CrossRef] | [PubMed]
 
Madden  PA;  Bucholz  KK;  Dinwiddie  SH;  Slutske  WS;  Bierut  LJ;  Statham  DJ;  Dunne  MP;  Martin  NG;  Heath  AC:  Nicotine withdrawal in women.  Addiction 1997; 92:889—902
[CrossRef] | [PubMed]
 
Pergadia  ML;  Agrawal  A;  Heath  AC;  Martin  NG;  Bucholz  KK;  Madden  PA:  Nicotine withdrawal symptoms in adolescent and adult twins.  Twin Res Hum Genet 2010; 13:359—369
[CrossRef] | [PubMed]
 
Glassman  AH;  Covey  LS;  Stetner  F;  Rivelli  S:  Smoking cessation and the course of major depression: a follow-up study.  Lancet 2001; 357:1929—1932
[CrossRef] | [PubMed]
 
Kendler  KS;  Neale  MC;  MacLean  CJ;  Heath  AC;  Eaves  LJ;  Kessler  RC:  Smoking and major depression: a causal analysis.  Arch Gen Psychiatry 1993; 50:36—43
[PubMed]
[CrossRef]
 
Saccone  SF;  Pergadia  ML;  Loukola  A;  Broms  U;  Montgomery  GW;  Wang  JC;  Agrawal  A;  Dick  DM;  Heath  AC;  Todorov  AA;  Maunu  H;  Heikkila  K;  Morley  KI;  Rice  JP;  Todd  RD;  Kaprio  J;  Peltonen  L;  Martin  NG;  Goate  AM;  Madden  PA:  Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples.  Am J Hum Genet 2007; 80:856—866
[CrossRef] | [PubMed]
 
Loukola  A;  Broms  U;  Maunu  H;  Widén  E;  Heikkilä  K;  Siivola  M;  Salo  A;  Pergadia  ML;  Nyman  E;  Sammalisto  S;  Perola  M;  Agrawal  A;  Heath  AC;  Martin  NG;  Madden  PA;  Peltonen  L;  Kaprio  J:  Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background.  Pharmacogenomics J 2008; 8:209—219
[CrossRef] | [PubMed]
 
Breen  G;  Webb  BT;  Butler  AW;  van den Oord  EJCG;  Tozzi  F;  Craddock  N;  Gill  M;  Korszun  A;  Maier  W;  Middleton  L;  Mors  O;  Owen  MJ;  Cohen-Woods  S;  Perry  J;  Galwey  NW;  Upmanyu  R;  Craig  I;  Lewis  CM;  Ng  M;  Brewster  S;  Preisig  M;  Rietschel  M;  Jones  L;  Knight  J;  Rice  J;  Muglia  P;  Farmer  AE;  McGuffin  P:  A genome-wide significant linkage for severe depression on chromosome 3: the Depression Network Study.  Am J Psychiatry  (published online  May 16, 2011; doi:10.1176/appi.ajp.2011.10091342)
 
Bucholz  KK;  Cadoret  R;  Cloninger  CR;  Dinwiddie  SH;  Hesselbrock  VM;  Nurnberger  JI  Jr;  Reich  T;  Schmidt  I;  Schuckit  MA:  A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA.  J Stud Alcohol 1994; 55:149—158
[PubMed]
 
Hesselbrock  M;  Easton  C;  Bucholz  KK;  Schuckit  M;  Hesselbrock  V:  A validity study of the SSAGA: a comparison with the SCAN.  Addiction 1999; 94:1361—1370
[CrossRef] | [PubMed]
 
American Psychiatric Association:  Diagnostic and Statistical Manual of Mental Disorders , 4th ed (DSM-IV).  Washington, DC,  American Psychiatric Publishing, 1994
 
Cottler  LB;  Robins  LN;  Grant  BF;  Blaine  J;  Towle  LH;  Wittchen  HU;  Sartorius  N:  The CIDI-core substance abuse and dependence questions: cross-cultural and nosological issues: the WHO/ADAMHA Field Trial.  Br J Psychiatry 1991; 159:653—658
[CrossRef] | [PubMed]
 
Pergadia  ML;  Agrawal  A;  Loukola  A;  Montgomery  GW;  Broms  U;  Saccone  SF;  Wang  JC;  Todorov  AA;  Heikkilä  K;  Statham  DJ;  Henders  AK;  Campbell  MJ;  Rice  JP;  Todd  RD;  Heath  AC;  Goate  AM;  Peltonen  L;  Kaprio  J;  Martin  NG;  Madden  PA:  Genetic linkage findings for DSM-IV nicotine withdrawal in two populations.  Am J Med Genet B Neuropsychiatr Genet 2009; 150B:950—959
[CrossRef] | [PubMed]
 
Kong  A;  Gudbjartsson  DF;  Sainz  J;  Jonsdottir  GM;  Gudjonsson  SA;  Richardsson  B;  Sigurdardottir  S;  Barnard  J;  Hallbeck  B;  Masson  G;  Shlien  A;  Palsson  ST;  Frigge  ML;  Thorgeirsson  TE;  Gulcher  JR;  Stefansson  K:  A high-resolution recombination map of the human genome.  Nat Genet 2002; 31:241—247
[PubMed]
 
Abecasis  GR;  Cherny  SS;  Cookson  WO;  Cardon  LR:  MERLIN: rapid analysis of dense genetic maps using sparse gene flow trees.  Nat Genet 2002; 30:97—101
[CrossRef] | [PubMed]
 
Kong  A;  Cox  NJ:  Allele-sharing models: LOD scores and accurate linkage tests.  Am J Hum Genet 1997; 61:1179—1188
[CrossRef] | [PubMed]
 
Whittemore  AS;  Halpern  J:  A class of tests for linkage using affected pedigree members.  Biometrics 1994; 50:118—127
[CrossRef] | [PubMed]
 
North  BV;  Curtis  D;  Sham  PC:  A note on the calculation of empirical p values from Monte Carlo procedures.  Am J Hum Genet 2002; 71:439—441
[CrossRef] | [PubMed]
 
North  BV;  Curtis  D;  Sham  PC:  A note on calculation of empirical p values from Monte Carlo procedure.  Am J Hum Genet 2003; 72:498—499
[CrossRef] | [PubMed]
 
Medland  SE;  Nyholt  DR;  Painter  JN;  McEvoy  BP;  McRae  AF;  Zhu  G;  Gordon  SD;  Ferreira  MA;  Wright  MJ;  Henders  AK;  Campbell  MJ;  Duffy  DL;  Hansell  NK;  Macgregor  S;  Slutske  WS;  Heath  AC;  Montgomery  GW;  Martin  NG:  Common variants in the trichohyalin gene are associated with straight hair in Europeans.  Am J Hum Genet 2009; 85:750—755
[CrossRef] | [PubMed]
 
Edlund  CK;  Lee  WH;  Li  D;  van den Berg  DJ;  Conti  DV:  Snagger: a user-friendly program for incorporating additional information for tagSNP selection.  BMC Bioinformatics 2008; 9:174
[CrossRef] | [PubMed]
 
Boomsma  DI;  Willemsen  G;  Sullivan  PF;  Heutink  P;  Meijer  P;  Sondervan  D;  Kluft  C;  Smit  G;  Nolen  WA;  Zitman  FG;  Smit  JH;  Hoogendijk  WJ;  van Dyck  R;  de Geus  EJ;  Penninx  BW:  Genome-wide association of major depression: description of samples for the GAIN Major Depressive Disorder Study: NTR and NESDA biobank projects.  Eur J Hum Genet 2008; 16:335—342
[CrossRef] | [PubMed]
 
Muglia  P;  Tozzi  F;  Galwey  NW;  Francks  C;  Upmanyu  R;  Kong  XQ;  Antoniades  A;  Domenici  E;  Perry  J;  Rothen  S;  Vandeleur  CL;  Mooser  V;  Waeber  G;  Vollenweider  P;  Preisig  M;  Lucae  S;  Müller-Myhsok  B;  Holsboer  F;  Middleton  LT;  Roses  AD:  Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts.  Mol Psychiatry 2010; 15:589—601
[CrossRef] | [PubMed]
 
Vink  JM;  Beem  AL;  Posthuma  D;  Neale  MC;  Willemsen  G;  Kendler  KS;  Slagboom  PE;  Boomsma  DI:  Linkage analysis of smoking initiation and quantity in Dutch sibling pairs.  Pharmacogenomics J 2004; 4:274—282
[CrossRef] | [PubMed]
 
McMahon  FJ;  Akula  N;  Schulze  TG;  Muglia  P;  Tozzi  F;  Detera-Wadleigh  SD;  Steele  CJ;  Breuer  R;  Strohmaier  J;  Wendland  JR;  Mattheisen  M;  Mühleisen  TW;  Maier  W;  Nöthen  MM;  Cichon  S;  Farmer  A;  Vincent  JB;  Holsboer  F;  Preisig  M;  Rietschel  MBipolar Disorder Genome Study (BiGS) Consortium:  Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1.  Nat Genet 2010; 42:128—131
[CrossRef] | [PubMed]
 
References Container
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