Chromosome 13 Workshop Report

Chair: Nicholas Barden1*; Co-Chair: Jean Morissette2

1Neuroscience, Laval University Hospital Research Centre, Quebec, Canada2Laval University Hospital Research Centre, Quebec, Canada

Participants:Katerina Blaveri (Molecular Psychiatry Laboratory, University College London Medical School,

London, U.K.)Sevilla Detera-Wadleigh (National Institute of Mental Health (NIMH), Bethesda, Maryland)Pablo Gejman (NIMH, Bethesda, Maryland)John Kelsoe (Department of Psychiatry, University of California-San Diego, California)Richard Todd (Departments of Psychiatry and Genetics, Washington University School of Medicine,

St. Louis, Missouri)

Contributor:Jean-Louis Blouin (Medical Genetics, Geneva University Cantonal Hospital and School of Medicine,

Geneva, Switzerland)

Evidence was presented that provided sup-port for linkage in a relatively broad telo-meric region of chromosome 13. A signifi-cant overlap for positive markers linked toboth bipolar disorder and schizophrenia oc-curred in this area. Am. J. Med. Genet. (Neu-ropsychiatr. Genet.) 88:260–262, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: Chromosome 13; Bipolar dis-order; Schizophrenia; link-age analysis

Presentations covering bipolar disorder and schizo-phrenia were heard.

BIPOLAR DISORDER

Three groups presented data on bipolar disorder.Richard Todd presented results from a completed ge-

nome screen for association of chromosomal regionswith bipolar affective disorder in a large outbred pedi-gree identified in the Midwest of the United States.One hundred twenty-eight members of the family wereincluded in the genome scan including 13 individualsassigned a diagnosis of either schizoaffective, mania, orbipolar I disorder (BP) (via SADS-L interviews con-ducted twice over a two- to five-year period) [Gerhardet al., 1998]. In this pedigree, there was unilineal in-heritance and no evidence for age effects in the onset ofbipolar disorder or depression. Genotyping results

were analyzed for linkage using FASTLINK programsand a model specified with a population frequency of0.1%, penetrance of 60% for heterozygous and homozy-gous carriers of the disease allele, and a 1% phenocopyincidence. All markers were also analyzed nonpara-metrically using SimIBD.

Using two-point lod scores and identity by descentmeasures, he analyzed 14 chromosome 13 markerswith an average spacing of 9.3 cM and a mean infor-mation content of 62%. For two-point linkage analysisusing hierarchical models including BP, BP and bipolarII disorder, or BP and bipolar II and major depressivedisorder, recurrent, there were no lod scores observedabove 1.0. Similarly, for SimIBD analysis, there wereno significant values for BP only. One marker(D13S321) (Fig. 1 [1]) showed marginally significantp-values for models including bipolar II or bipolar IIplus depression. In this case, however, flanking mark-ers were not significant. He concluded that in this pedi-gree there was no evidence for susceptibility loci to bi-polar affective disorder.

Sevilla Detera-Wadleigh presented linkage data on22 multiply affected pedigrees containing about 400genotyped individuals. Twenty-one markers spaced atabout 5 cM were used from D13S787 to D13S285 (Fig.1 [2]). Within a region encompassed by D13S793 andD13S1266, the highest pointwise IBD marker score on13q32 was 0.64 (P 4 0.0002), under affection statusmodel I (ASMI) which includes BPI, BPII with majordepression, and schizoaffective disorder (SA). Maximalmultipoint lod by GENEHUNTER PLUS using nuclearfamilies was 3.5 (P 4 0.000028), under ASMII (ASM Iplus recurrent unipolar depressive disorder [UP]) [De-tera-Wadleigh et al., 1998].

John Kelsoe presented data obtained with 20 fami-lies from the general North American population. In

*Correspondence to: Nicholas Barden, Laval Unviersity Hospi-tal Research Centre, Quebec, Canada. E-mail: barden@crchul.ulaval.ca

American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:260–262 (1999)

© 1999 Wiley-Liss, Inc.

the total 164 subjects there were 46 cases of BP and 28cases of recurrent major depression (RD). Parametricanalyses were performed using two diagnostic models(BP only, BP+RD) and three genetic models (autosomaldominant 85% penetrance, autosomal dominant 50%penetrance, autosomal recessive 50% penetrance) atthe loci D13S787, D13S894, D13S325, D13S153,

D13S800, D13S793, D13S154, D13S770, D13S1240,D13S779, D13S225, D13S796, D13S173, and D13S285.Highest lod scores were obtained at D13S154 (Fig. 1[3]) (lod 2.40 at Q 0.01) and at D13S796 (lod 2.34 at Q0.01) using a recessive model of transmission and in-cluding all BP and RD as affected. Intervening markerscovering a distance of 8 cM also gave support, but thiswas not consistent when the same parametric modelwas used [Kelsoe et al., 1998].

SCHIZOPHRENIA

Katerina Blaveri reported on some preliminary in-vestigations on markers at the loci D13S119 (Fig. 1[4]), D13S128, and D13S144 that gave the most posi-tive lod score in a previous linkage study by [Lin et al.,1997]. They studied a sample of 23 multiply affectedIcelandic and English schizophrenia families charac-terized by their large family size and their potential toresolve heterogeneity of linkage. Results were analyzedusing two affection models (“core schizophrenia,” de-noted DOMS, consists of schizophrenia and unspecifiedfunctional psychosis; “schizophrenia spectrum,” de-noted DOMSS, consists additionally of schizoid andschizotypal personality disorder according to Diagnos-tic and Statistical Manual of Mental Disorders (DSM-IIIR) criteria and schizotypal features according to theResearch diagnostic criteria (RDC). Of the 385 indi-viduals in these 23 pedigrees, 95 fell into the DOMScategory and an additional 17 fell into the DOMSS cat-egory. Using these disease models a maximum lodscore of 1.08 with the marker D13S144 using a “spec-trum” definition of being affected in a sample of 23multiplex families was found. The recombination frac-tion for this lod was 10% and the proportion of familiespossibly linked to D13S144 was 45.

Pablo Gejman presented ASPEX data for 15 markerstyped in 76 families showing schizophrenia. No signifi-cant results were obtained.

Material was provided by Jean-Louis Blouin derivedfrom linkage studies with 105 families (54 in the origi-nal sample, 363 genotyped, 147 affected: 51 in the fol-low-up sample [replication], 289 genotyped, 134 af-fected). These families were of mixed origins (75 Euro-pean descent, 6 African-American, 5 Ashkenazim, 1Amish, 10 Italian, 5 Greek, and 3 Polish). A total of 652individuals were genotyped. Affected phenotype wasDSM-IV schizophrenia and schizoaffective disorders(other psychotic disorders or a schizophrenia spectrumof personality disorders were not included, nor wereindividual with no consensus diagnostic by two inde-pendent psychiatrists). Twenty-eight markers wereanalyzed on chromosome 13 using parametric and non-parametric (Genehunter) methods. The best score onthe original sample was seen at D13S174 (Fig. 1 [5])assuming heterogeneity (parametric ZH 4 3.19 [reces-sive], ZH 4 1.84 [dominant]; nonparametric NPL Z-all4 4.18, p 4 0.0002). An NPL A-all of 2.36 (p 4 0.023)was obtained in the follow-up sample [Blouin et al.,1998].

Fig. 1. Modified sex-average linkage map from Broman et al. [1998]. Alladded markers, appearing on right side, have been mapped according tothe genetic location database [Collins et al., 1996]. (1) Todd et al.; (2)Detera-Wadleigh et al.; (3) Kelsoe et al.; (4) Blaver et al. and Lin et al.; (5)Blouin et al.

Chromosomes 13 and 17 Workshop 261

CONCLUSIONS

This chromosome was the focus of a report at the1997 World Congress of Psychiatric Genetics. The ma-jority of presentations on both bipolar disorder andschizophrenia given here were focused on the regionaround the 5HT2A gene. A conclusion was reached thatinsufficient positive results prevented the conclusion ofany linkage or association to this locus. In contrast,with the exception of the results of Dr. Blaveri et al. inschizophrenia families and which by themselves arenot sufficiently strong to support linkage, this loci wasignored this year. It remains, therefore, a locus thatcannot be considered as positive.

The majority of presentations this year were local-ized to a region more telomeric to the 5HT2A locus.These were on both bipolar disorder and on schizophre-nia and, while not all presentations supported linkage,there was indication for a major overlap of positivemarkers for these two disorders. Neither the results ofKelsoe and Detera-Wadleigh on bipolar disorder northose of Blouin on schizophrenia are of sufficientstrength by themselves to declare a susceptibility lo-cus. However, together, and particularly those ofBlouin et al., they do underline the importance of fur-ther investigations in this area.

REFERENCES

Blouin JL, Dombroski BA, Nath SK, Lasseter, VK, Wolyniec PS, NestadtG, Thornquist M, Ulrich G, McGrath J, Kasch L, Lamacz M, ThomasMG, Gehrig C, Radhakrishna U, Snyder SE, Balk KG, Neufeld K,Swartz KL, KeMarchi N, Papadimitriou GN, Dikeon DG, Stefanis CN,Chakravasti A, Childs B, Housman DE, Kazazian HH, AntonasakisSE, Palver AE. 1998. Schizophrenia susceptibility loci on chromosomes13q32 and 8p21. Nature Genet 20:70–73.

Broman KW, Murray JC, Sheffield VA, White RL, Weber JL. 1998. Com-prehensive human genetic maps: individual and sex-specific variationin recombination. Am J Hum Genet 63:861–869.

Collins A, Frezal J, Teague J, Morton NE. 1996. A metric map of humans:23,500 loci in 850 bands. Proc Natl Acad Sci USA 93:14771–14775.

Detera-Wadleigh SD, Yoshikawa T, Padigaru M, Berritini WH, Badner JA,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.

Gerhard DS, LaBuda MC, Nguyen LT, Armstrong C, Todd RD. 1998. Re-sults of a genome screen for genes predisposing for major affectivedisorder in two large kindreds. Am J Med Genet 81:462.

Kelsoe, JR, Loetscher E, Spence MA, Foguet M, Sadovnick AD, Remick RA,Flodman P, Masser D, Ungerleider S, Rapaport MH, WLW, LuebbertH. 1998. A genome survey of bipolar disorder indicates a susceptibilitylocus on chromosome 22. Am J Med Genet 81:461.

Lin MW, Sham P, Hwu HG, Collier D, Murray R, Powell JF. 1997. Sug-gestive evidence for linkage of schizophrenia to markers on chromo-some 13 in Caucasian but not Oriental populations. Hum Genet 99:417–420.

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