Chromosome Workshops 1998:Current State of Psychiatric Linkage

Lynn E. DeLisi1* and Timothy J. Crow2

1Department of Psychiatry, Health Sciences Center, State University of New York, Stony Brook, New York2University Department of Psychiatry, The Warneford Hospital, Oxford University, Headington, U.K.

The Chromosome Workshops were initiated in 1997at The Vth World Congress of Psychiatric Genetics andtheir subsequent reports published in Psychiatric Ge-netics [Crow and DeLisi, 1998]. The purpose was togather together existing data, whether the focus ofpublications or not, for each major genomic region thathad been proposed as a possible location for a gene forany major psychiatric disorder. The reports attemptedto integrate all known existing data onto a “psychiatricmap” that would define the certainty and consistency ofseveral publicized findings, as well as inconsistenciesand reported “replications.” These summaries thus in-cluded regions on chromosomes 3, 4, 5, 6, 8, 11, 13, 18,21, 22, and X. We [Crow and DeLisi, 1998] then sum-marized the known complete genome scans for bipolardisorder and schizophrenia to obtain a genome-wideperspective and examine the consistencies across in-vestigative groups.

From the previous workshop reports, it can be con-cluded that no consistent findings for any psychiatricdisorder were found on chromosomes 3 [Nimgaonkar,1998]. It was suggested that chromosome 4p might con-tain a susceptibility locus for bipolar disorder, schizo-phrenia, and alcoholism combined [Kennedy andMacciardi, 1998]; the strongest region on chromo-some 5 was 5q23.3-q31.1 for schizophrenia alone[Crowe and Vieland, 1998]; and that a locus for schizo-phrenia on 6p22-24 (despite the spread of findings wellover a 40 cM range) remained the strongest replicatedpositive so far in psychiatric genetics [Nurnberger andForoud, 1998]. Furthermore, chromosome 8p was re-ported as significantly positive for both schizophreniaand harm-avoidance personality traits in alcoholism[Wildenauer and Schwab, 1998], chromosome 11p nearthe DRD4 locus for alcoholism [Owen and Craddock,1998], chromosome 13 at several loci throughout thechromosome [Barden and Morissette, 1998], whereasno one region on all of chromosome 18 could be ex-cluded for linkage to bipolar disorder and the pericen-tromeric region for schizophrenia [Van Broeckhovenand Verheyen, 1998]. Chromosome 21q21-22 was con-

sidered significantly positive in multiple studies of bi-polar families only [Gurling, 1998] and chromosome22q within the VCFS deletion region was considered ofinterest for schizophrenia [Levinson et al., 1998]. The Xchromosome remained of interest pericentromeric andfurther distal on the q arm for schizophrenia and bipo-lar disorder, respectively, although it was noted thatthese may be “loci of modest susceptibility” [Paterson,1998].

From a cautionary perspective viewing results fromthe genome scans [Crow and DeLisi, 1998], we notedthe inconsistencies for all these putative regions acrossstudies, with many negative reports being dismissed ashaving small numbers or just missing the locus, whilstpositive findings with small numbers of families [i.e.,Pulver et al., 1995] were not being replicated in largersamples [i.e., Williams et al., 1998]. Many of these find-ings spread well over half the genome, and are likely tobe false positives, yet how was one to determine whichones? We had hopes that progress over the followingyear would eliminate some false positives and thatthese workshops would have impact on the direction offuture efforts.

The reports that follow are a result of this endeavor.At the VIth World Congress of Psychiatric Genetics(Bonn, Germany, October 7–10, 1998) the workshopswere extended to cover the entire genome. In addition,we have summarized the latest findings now availablefor genome-wide scans (Table I) and revised ourmethod for reporting to allow each study to provide itsown internal control by presenting the four most posi-tive regions for each regardless of the actual lod score.We concluded this was the best way of comparing ge-nome scans since studies varied considerably in num-bers of families, informativeness of families, number ofmarkers, type of markers, and genomic spacing.

What has been added to the previous reports? Thechromosome 21 workshop reported strong evidencefor a locus for bipolar disorder within 21q, but we no-tice that the bipolar genome scans fail to identify 21qas one of their four highest scoring regions. Overall,the more chromosomes that were added for workshops,the more positive findings emerged. On the X chromo-some any positive findings from the last report wereseen as weak and possibly due to distorted sex ratios.

*Correspondence to: L.E. Delisi, Department of Psychiatry,Health Sciences Center (T-10), SUNY, Stony Brook, Stony Brook,New York 11794. E-mail: LdeLisi@ccmail.sunysb.edu

American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:215–218 (1999)

© 1999 Wiley-Liss, Inc.

Are there any patterns of consistency among thewhole genome scans that were not apparent a year ago?Still findings are scattered throughout the genome(Table I). Chromosomes 7, 9, 14, 17, and 19 have yet tobe putatively linked to psychiatric disease. Still, we donot know which ones of the positive reports are simplychance findings (false positives). None yet appearstrong enough to invest time and resources into se-quencing the surrounding region in the hope of cloningthe psychosis gene, although some research groupsmay have already embarked upon this endeavor. Viewsvary widely from the notion that there is one majorgene for all of psychosis, to one major gene within somefamilies but several different genes within separatepopulations, to the concept that a few interacting genesare necessary for expression of the disorder withinone individual. If the multitude of positive regions de-scribed represent regions of true psychosis vulnerabil-ity loci, this would surely support the latter concept.

Other researchers have adopted the strategy of iden-tifying cohorts of families from isolated homogeneouspopulations derived from a small founder population afew centuries back as valuable resources in which to

test the validity of the findings from heterogeneouspopulations. Such cohorts include families from Ice-land, Northern Sweden, Costa Rica, the AmericanAmish, and the south Pacific island of Palau. If onemajor gene for psychosis exists, it should be more easilydetectable in families from these populations, unlessthe frequency of spontaneous mutations is high. Wethus have also summarized these reports, as presentedby October 1998, for evidence of linkage (see Table II).Of note is the fact that an isolate in northeasternFinland gives entirely different results than a studyof the rest of the Finnish population by the same in-vestigators. Furthermore, different investigativegroups studying the same Amish families have differ-ent findings. Thus, contrary to what might have beenhoped, these isolates are not providing definitiveanswers.

At present, the linkage strategy is not yielding thestrong and consistent leads that had been hoped for 5to 10 years ago. Other approaches, e.g., through patho-physiological mechanisms, may have to be pursued.Without a hypothesis there may be no way ahead.

TABLE I. Positive Chromosome Regions (For Highest From Each Study) From Independent Genomewide Screens forSchizophrenia and Bipolar Disorder. Only Chromosomes Where at Least One Study Had a Positive Finding are Shown

Studies* N4 1q 2p 2q 3q 4p 4q21- 5p 5q 6p24- 6q 7q 8p23- 9q 10p(et al.) 26 22 21 13–14

SchizophreniaBlouin (1998) 54 − − − − − − − − − − − + − −Faraone (1998) 43 − + − − − − − − − − + − − +Kaufman (1998) 30 − − − − − − − − − + − + + −Levinson (1998) 43 − + + − − + − − − − − − − −Moises (1995) 5 − + + − + + − − − − − − − −Shaw (1998) 70 − + − − − − + − − − − − − −Williams (1998) 200 − − − − + − − − − − − − − −Straub (1997) 265 − − − − − − − + + − − + − +Wildenauer (1998) 72 − − − − − − − − + − − − − +BipolarCoon (1993) 8 − − − − + − − ++ − − − − − −Detera-Wad. (1998) 22 + − − − − − − − − − − − − −Foroud (1998) 97 − − − − − − − − − + − − − +Kelsoe (1998) 20 − − − + − − + − − − − − − −Liu (1998) 57 − + − − − + − − − − − + − −

Studies*(et al.)

10q11-23 11p-q 12p 13q32 14q 15p

16q13-22 17 18p 18q 20q 21q

22q11-12 Xcen

Schizophrenia:Blouin − − − + + − − − − − − − +Faraone + − − − − − − − − − − − − −Kaufman − − − − − + − − − − − − − −Levinson + − − − − − − − − − − − − −Moises − − − − − − − − − − − − − −Shaw − − − − − − + − − − − − + −Straub − − − − − − − − − − − − − −Wildenauer − − − − − − − − + − − − +Williams − − − − − − − − − + + − − +Bipolar:Coon − + − − − − − − − − − − − −Detera-Wad. − − − + − − − − + − − − + −Foroud − − − − − − + − − − + − − −Kelsoe − − − + − − − − − − − + −Liu − − − − − − − + − − − − −

*NIMH initiative; +, one of the four highest scores; −, did not rank in four highest.

216 DeLisi and Crow

REFERENCES

Barden N, Morissette J. 1998. Chromosome 13 workshop. Psychiatr Gen8:93–96.

Blouin J-L, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, NestadtG, Thornquist M, Ullrich G, McGrath J, Kasch L, Lamancz M, ThomasMG, Gehrig C, Radhakrishna U, Snyder SE, Balk KG, Neufeld K,Swartz KL, DeMarchi N, Popadimitriou N, Dikeos G, Sefanis N,Charavarti A, Childs B, Housman DE, Kazazian HH, Antonarakis SE,Pulver AE. 1998. Schizophrenia susceptibility loci on chromosome13q32 and 8p21. Nature Genet 20:70–73.

Coon H, Jensen S, Hoff M, Holik J, Plaetke R, Reimherr F, Wender P,Leppert M, Byerley W. 1993. A genome-wide search for genes predis-posing to manic-depression, assuming autosomal dominant inheri-tance. Am J Human Genet 52:1234–1249.

Coon H, Myles-Worsley M, Tiobech J, Hoff M, Rosenthal J, Bennett P,Reimherr F, Wender P, Dale P, Poloi A, Byerley W. 1998. Evidence fora chromosome 2p13-14 schizophrenia susceptibility locus in familiesfrom Palau, Micronesia. Mol Psychiatry 3:521–527.

Crow TJ, DeLisi LE. 1998. The chromosome workshops at the 5th Inter-national Congress of Psychiatric Genetics—the weight of the evidencefrom genome scans. Psychiatric Genet 8:59–61.

Crowe RR, Vieland V. 1998. Chromosome 5 workshop. Psychiatric Genet8:73–78.

Detera-Wadleigh SD, Yoshikawa T, Padigaru M, Berrettini WH, BadnerJA, Sanders A, Goldin LR, Turner G, Rollins DY, Moses T, Esterling L,Gershon ES. 1998. Genome screen and candidate gene analysis in bi-polar disorder. Am J Med Genet 81:463.

Ekelund J, Licktermann D, Hovatta I, Terwilliger J, Suvisaari J, VaisanenL, Kokko-Sahin M-L, Juvonen H, Lonnqvist J, Peltonen L. 1998. Asearch for schizophrenia loci in multiple study samples in Finland. AmJ Med Genet 81:453.

Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez B, HampeC, Zambutto T, Schmitt K, Meyer J, Markel P, Lee H, Harkavy-Friedman J, Kaufmann C, Cloninger CR, Tsuang MT. 1998. Genomescan of European-American schizophrenia pedigrees: results of theNIMH genetics initiative and millennium consortium. Am J Med Genet81:290–295.

Foroud T, Castellucio PF, Koller DL, Edenberg HJ, Goate A, Detera-Wadleigh S, Stine OC, McMahon FJ, McInnis MG, Rice J, Blehar M,GOldin LR, Badner J, Guroff J, Reich T, DePaulo JR, Gershon E, Nurn-berger JI. 1998. Genomewide scan of affected relative pairs using theNIMH genetics initiative bipolar affective disorder pedigrees. AM JMed Genet 81:462.

Gerhard DS, LaBuda MC, Nguyen LT, Armstrong C, Todd RD, Reich T.1998. Results of a genome screen for genes predisposing for major af-fective disorder in two large kindreds. Am J Med Genet 81:462–463.

Ginns EI, Ott J, Egeland JA, Allen CR, Farnn CS, Pauls DL, WeissenBachoff J, Carulli JP, Falls KM, Keith TP, Pauls SM. 1996. A genome-wide search for chromosomal loci linked to bipolar affective disorder inthe old order Amish. Nature Genet 12:431–435.

Gurling H. 1998. Chromosome 21 workshop. Psychiatric Genet 8:109–113.

Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R,Juvonen H, Kokko-Sahin M–L, Vaisanen L, Mannila H, Lonnqvist J,Peltonen L. 1998. A genome-wide search for schizophrenia genes in aninternal isolate of Finland suggesting multiple susceptibility loci. Am JMed Genet 81:453–454.

Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD,Meyer J, Zambuto CT, Schmitt K, Cox-Matise T, Harkavy-Friedman J,Hampe C, ee H, Shore D, Wynne D, Faraone SV, Tsuang MT, CloningerCR. 1998. Genetics initiative millenium schizophrenia consortium:linkage analysis of African-American pedigrees. Am J Med Genet 81:282–289.

Kelsoe JR, Loetscher E, Spense MA, Foguet M, Sadovnick AD, Remick RA,Flodman P, Masser D, Ungerleider S, Rapaport MH, Wishart WL, Lu-ebert H. 1998. A genome survey of bipolar disorder indicates a suscep-tibility locus on chromosome 22. Am J Med Genet 81:461–462.

Kennedy JL, Macciardi FM. 1998. Chromosome 4 workshop. PsychiatricGenet 8:67–71.

LaBuda MC, Maldonado M, Marshall D, Otten K, Gerhard DS. 1996. Afollow-up report of a genome search for affective disorder predispositionloci in the old order Amish. Am J Hum Genet 59:1343–1362.

Levinson DF, Coon H. 1998. Chromosome 22 workshop. Psychiatric Genet8:115–120.

Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, KirbyA, Black DW, Jilverman JM, Endicott J, Shrpe L, Mohs RC, Siever LJ,Walters MK, Lennon DP, Jones HL, Nertney DA, Daly MJ, Gladis M,Mowry BJ. 1998. Genome scan of schizophrenia. Am J Psychiatry 155:741–750.

Liu J, Aita VM, Knowles JA, Terwilliger JD, Baltazar R, Grunn A, Yun O,Loth JE, ALexander JR, Lerer B, Endicott J, Wang Z, Penchaszadeh G,Gilliam TC, Baron M. 1998. A genome-wide scan for bipolar affectivedisorder. Am J Med Genet 81:462.

McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S, Rojas E,Spesny M, Baharloo S, Blankenship K, Peterson A, Tyler D, Shimayo-shi N, Tobey C, Batki S, Vinogradov S, Mesa L, Gallegos A, Fournier E,Smith LB, Barondes SH, Sandkuijl LA, Freimer NB. 1996. A complete

TABLE II. Genomewide Screens of Genetic Isolate Populations

Chromosomal Region With Reported Suggestions of LinkageN 1q 4p 4q 5q 6p 8p 9q 11p 12p 12q 18p 18q 20p 21q Xp

SchizophreniaIceland

Moises et al. (1998) 162a − − − − − + − − − − − − − − −Finland

Hovatta et al. (1998)b 20 + − + − − − + − − − − − − − +Ekelund et al. (1998)c 62 − − − + + + − − − − − − + − −

N. SwedenWetterberg (1998) 1 − − − − − + − − − − − − − − −

PalauCoon et al. (1998)d 1 − − − − − − − − − − − − − − −

Bipolar DisorderAmish 1

LaBuda et al., Gerhard et al. (1996) − − − − − − − − − − + − − − −Ginns et al. (1996)e − − − − + − − − − − − − − − −Polymeroulos & Schaffer (1996)f − + − − + − + − − − − − − − −

Costa RicaMcInnes et al. (1996) 2 − − − − − − − + + − − + + − −

QuebecShink et al. (1998) 1 − − − + − − − − − + + − − + −

aparent-child pairs.bNortheastern Finland.cAll Finland.dalso 2pealso 13q and 15q.falso 19p.

Chromosome Workshops 1998 217

genome screen for genes predisposing to severe bipolar disorder in twoCosta Rican pedigrees. Proc Nat Acad Sci USA 93:13060–13065.

Moises HW, Yang L, Kristjamarson H, Wiese C, Byerley W, Macciardi F,Arolt V, Blackwood D, Liu X, Sjogren B, Aschauer HN, Hwu HG, JangK, Livesley WJ, Kennedy JL, Zoega T, Ivarsson O, Bui MT, Yu MH,Havsteen B, Commenges D, Weissenbach J, Schwinger E, GottesmanII, Pakstis AJ, Wetterberg L, Kidd KK, Helgason T. 1995. An interna-tional two-stage genome-wide search for schizophrenia susceptibilitygenes. Nature Genet 11:321–324.

Moises HW, Edwards JH, Matthiasson P, Jhala G, Kristbjarnarson H,Gottesman II, Karlsdottir-Waldorff F, Neubauer B, Zoega T, HelgasonT. 1998. Haplotype analysis of chromosome 8p and 15q in Icelandicschizophrenia patients. Am J Med Genet 81:471.

McInnis MG, MacKinnon DF, McMahon FJ, Foroud T, Edenberg HJ, GoateA, Detera-Wadleigh S, Stone OC, Rice J, Blehar M, Reich T, Gershon E,Nurnberger JI, Simpson SG, DePaulo JR. 1998. Evidence for a suscep-tibility locus for bipolar disorder on chromosome 11p11.5. Am J MedGenet 81:463.

Nimgaonkar VL. 1998. Chromosome 3 workshop. Psychiatric Genet 8:63–65.

Nurnberger JI, Foroud T. 1998. Chromosome 6 workshop. PsychiatricGenet 8:79–84.

Owen MJ, Craddock N. 1998. Chromosome 11 workshop. Psychiatr Genet8: 89–92.

Paterson AD. 1998. X-chromosome workshop. Psychiatric Genet 8:121–126.

Polymeropoulos MH, Schaffer AA. 1996. Scanning the genome with 1772microsatellite markers in search of a bipolar disorder susceptibilitygene. Mol Psychiatry 1:404–407.

Pulver AE, Lasseter VK, Kasch L, Wolyniec P, Nestadt G, Blouin JL,Kimberlaud M, Babb R, Vourlis S, Chen H, LaLioti M, Morris MA,Karayioorgou M, Ott J, Meyers D, Antonarakis SE, Housman D, Ka-zazian HH. 1995. Schizophrenia: a genome scan targets chromosome

3p and 8p as potential sites of susceptibility genes. Am J Med Genet60:252–260.

Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J, Laval SH,Vita A, De Hert M, Cardon LR, Crow TJ, Sherrington R, DeLisi LE.1998. A genome-wide search for schizophrenia susceptibility genes. AmJ of Medical Genetics 81:364–376.

Shink E, Morissette J, Rochette D, Bordeleau L, Plante M, Villeneuve A,Barden N. 1998. Bipolar affective disorder susceptibility loci on chro-mosomes 5 and 21: heterogeneity in a homogeneous population in Que-bec. Am J Med Genet 81:541–542.

Straub RE, MacLean CJ, Martin RB, Ma Y, Myakishov MV, Harris-Ker C,Webb BT, O’Neill A, Welsh D, Kendler KS. 1998. Schizophrenia locusmay be located in region 10p15–p11. Am J of Med Genet 81:296–301.

Straub RE, MacLean CJ, O’Neill FA, Walsh D, Kendler KS. 1997. Genomescan for schizophrenia genes: a detailed progress report in an Irishcohort. Am J Med Genet 74:558.

Van Broeckhoven C, Verheyen G. 1998. Chromosome 18 workshop. Psy-chiatric Genet 8:97–108.

Wetterberg L, Peltonen L, Moises H, Kidd K, Sjogren B, Ekelund J, JhalaG, Neubauer B, Yang L, Sirugo G, Pakstis A. 1998. Search for schizo-phrenia loci in a Swedish geographic isolate. Am J Med Genet 81:470.

Wildenauer DB, Schwab SG. 1998. Chromosome 8 workshop. PsychiatricGenet 8:85–87.

Wildenauer DB, Schwab SG, Hallmayer J, Lerer B, Albus M, Borrman M,Lichtermann D, Dreikorn B, Hanses C, Eckstein GN, Zill P, Honig S,Kanya K, Segman R, Ebstein RE, Trixler M, Rietschel M, Maier W.1998. Genome scan for autosomal genes conferring risk to schizophre-nia in a German/Israeli sample. Am J Med Genet 81:454.

Williams NM, Rees MI, Norton N, Holmans P, Fenton I, Cardno AG, Mur-phy KC, Jones LA, McCarthy G, Sanders R, McGuffin P, Owen MJ.1998. A two-stage sib-pair genome scan for schizophrenia susceptibilitygenes. Am J Med Genet 81:453.

218 DeLisi and Crow