Molecular Psychiatry (1997) 2, 200–210 1997 Stockton Press All rights reserved 1359–4184/97 $12.00 PERSPECTIVE Genetic linkage and bipolar affective disorder: progress and pitfalls M Baron Department of Psychiatry, Columbia University College of Physicians and Surgeons, and Department of Medical Genetics, New York State Psychiatric Institute, 722 West 168th Street, New York, NY, USA The history of linkage studies in bipolar affective disorder is a convoluted affair punctuated by upswings and setbacks, hope and skepticism. Advances in genomics and statistical tech- niques, and the availability of well-characterized clinical samples, have bolstered the search for disease genes, leading to a new crop of findings. Indeed, recent reports of putative loci on chromosomes 18, 21, X, 4, 6, 13 and 15 have rekindled a sense of optimism. The new findings are reviewed and scrutinized, with implications for future research. Keywords: molecular genetics; DNA markers; genes; linkage analysis; bipolar disorder Linkage studies of bipolar affective disorder (manic nostic procedures and in statistical techniques appli- depression) have charted an unsteady course marred cable to complex traits.4–15 The availability of dense by fits and starts.1 Findings that appeared at first unas- genomic maps and suitable clinical samples is an sailable could not be replicated or faltered on further added asset. Indeed, the emergence of promising new scrutiny of the evidence. The highs and lows of this findings in the last 2 years may signal the turning of decades-long search were aptly dubbed ‘a manic the tide, though the problems posed for geneticists are depressive history’:2 bouts of optimism alternating far from over. In this article I review and critique the with dashed expectations. This predicament is not new findings, with an eye to future research. unique: in the wake of conflicting results and reversals of earlier findings, schizophrenia was nicknamed ‘a New findings graveyard for molecular geneticists’.3 Other complex disorders, which bear likeness to psychiatric disorders Several chromosomal regions have recently been by way of genetic and phenotypic uncertainties, were implicated in bipolar disorder: 18p16,17; 18q16–18; 21q19– similarly afflicted: some of the initial linkage findings 21;Xq22;4p23; and 6p, 13q and 15q.24 Altogether, eight in diabetes mellitus, Alzheimer’s disease, and breast putative loci are invoked in the latest spate of link- cancer were not compelling or readily interpretable, age reports. although subsequent studies firmed up the evidence. For the most part, the ill-fated findings in bipolar dis- Chromosome 18 order predate the molecular genetics era. This may be Berrettini et al16 reported evidence of linkage to the partly attributable to the low information content of pericentromeric region of chromosome 18. They con- classical markers and the dearth of polymorphisms that ducted a genomic scan in 22 North-American extended can serve to verify linkage assignments. But a host of pedigrees comprised of 365 individuals. Affected sib- other factors must be considered including the com- pair (ASP) analysis of 11 markers suggested linkage to plex inheritance of the disorder, leading to diminished the D18S21 locus (P = 0.0007); the affected-pedigree- power and difficulties in discerning true from false- member (APM) method also suggested linkage with positive findings; the involved procedures for data col- multilocus analysis of five pericentromeric markers lection and processing, causing variability among stud- (P , 0.0001 and P = 0.0007, depending on the weight- ies and proneness to error; selection bias; statistical ing function of allele frequencies). Lod score analysis artifacts, and misinterpretation of data.1,2,4–14 The did not yield statistically significant evidence of link- growing awareness of potential pitfalls has led to age, though modest lod scores were observed in some methodological advances in ascertainment and diag- pedigrees. The strongest results were obtained with a disease phenotype comprised of bipolar I and II, schi- zoaffective, and recurrent major depression. Correspondence: M Baron, Department of Psychiatry, Columbia In an attempt to replicate the Berrettini et al finding, University College of Physicians and Surgeons, and Department Stine et al17 studied 28 North-American nuclear famil- of Medical Genetics, New York State Psychiatric Institute, 722 West 168th Street, New York, NY, USA. E-mail: mb17Kcolum- ies consisting of 243 individuals, using 31 markers. bia.edu ASP analysis indicated excess allele sharing for 18p Received 17 October 1996; accepted 18 October 1996 markers, especially at D18S37 (P = 0.0003); addition- Genetic linkage and bipolar affective disorder M Baron 201 ally, excess sharing of paternally, but not maternally, evidence for linkage with either parametric or nonpara- transmitted alleles was observed for three markers on metric (APM and ASP) methods, though suggestive evi- 18q, especially at D18S41 (P = 0.0004). The evidence dence was obtained for some loci. Subdividing the for linkage to loci on both 18p and 18q was strongest pedigrees according to maternal versus non-maternal in the paternal pedigrees (those in which the illness transmission (the approach used by Stine et al17 and appeared to be transmitted from the father’s side of the Gershon et al25 to produce the strongest evidence for pedigree), in particular at D18S41 (P = 0.00002 using linkage) did not alter the pattern of results. ASP analysis, and a lod score of 3.51 at u = 0.0). The positive results were particularly pronounced using an Chromosome 21 affected phenotype similar to the one used by Berret- Straub et al19 reported a possible susceptibility locus tini et al.16 Stine et al concluded that their results con- at 21q22.3. They performed a preliminary genome scan firm Berrettini et al’s findings and, in addition, provide in 47 extended pedigrees obtained in the US and Israel support for a parent-of-origin effect. Subsequently, Ger- comprised of 937 genotyped individuals. A lod score shon et al25 reanalyzed the Berrettini et al16 pedigrees of 3.41 was observed at the PFKL locus; the lod score for parent-of-origin effect. Using ASP analysis, linkage was robust to marker allele frequencies, phenocopy to 18p-centromere markers was observed in ‘mixed’ rates, age-dependent penetrance, and changes in affec- paternal-maternal pedigrees, but not the maternal pedi- tion status (sensitivity analysis). Fourteen other mark- grees, especially at D18S32 (P , 0.00001), D18S56 ers in 21q22.3 were examined in this family with larg- (P = 0.00009) and D18S21 (P = 0.0007). Gershon et al25 ely positive lod score. Five other families also showed concluded that their results are consistent with those positive, though modest lod values with PFKL. The of Stine et al.17 maximum lod score for the entire pedigree series was Finally, Freimer et al18 found evidence for a bipolar 2.8. Extended sib-pair analysis (ESPA) did not yield a locus at 18q23 in two Costa Rican pedigrees obtained statistically significant result, but the single locus and from a genetically isolated population. The evidence, multilocus (PFKL and D21S171) APM method gave sig- obtained after a systematic genome scan had been com- nificant P-values (maximum value: ,10−6). The strong- pleted, was primarily based on the sharing of marker est results were obtained with an ‘intermediate’ pheno- haplotypes by individuals affected with bipolar I dis- type definition encompassing bipolar I and II, order, the narrowly defined phenotype of the illness. schizoaffective-manic, and recurrent major depression. Altogether, 14 markers spanning the 18q21–23 region Gurling et al20 studied 23 extended pedigrees (17 were studied. Association analyses yielded lod scores English; six Icelandic) comprised of 278 individuals. of 3.7 and 4.06 (both at u = 0.0) at D18S554 and They found a three-point lod score of 1.33, with PFKL D18S70, respectively. Overlap with the putative per- and D21S171. In addition, an overall lod score of 3.58 icentromeric region implicated by Berrettini et al16 was was observed when an oligogenic (two-locus) model excluded; overlap with the location proposed by Stine was used to analyze PFKL/D21S171 and the tyrosine et al17 did not appear likely but could not be excluded. hydroxylase (TH) locus on chromosome 11. (TH itself Other studies failed to turn statistically significant showed a lod score of 1.43 in these families.) ASP linkage to chromosome 18 markers. Maier et al26 stud- analysis was also suggestive of linkage with D21S171 ied six pericentromeric markers in five extended Ger- (P = 0.001). The largest lod scores and highest statisti- man families. Linkage was excluded using both lod cal significance were observed using a narrowly score and APM methods. Pauls et al27 examined four defined phenotype consisting of bipolar I and II. pericentromeric markers in three large Old Order Another set of results supportive of linkage to 21q Amish kindreds obtained from a homogeneous sample. was reported by Detera-Wadleigh et al21 who analyzed They excluded linkage to this region using both lod 22 extended North-American pedigrees consisting of score and ASP analyses. Debruyn et al28 examined 14 365 individuals. Using 18 markers on 21q, single-locus markers spanning the 18p11–18q23 region in two large ASP analysis detected a high proportion of alleles Belgian families. Using lod score analysis, there was shared identical by descent at nine loci (P = 0.049– no significant evidence for linkage; modest lod scores 0.0008). Multilocus analyses revealed locus trios with were observed for some markers in one family. Simi- excess allele sharing in: 1) the distal region between larly, ASP analyses did not yield statistically signifi- D21S270 and D21S171 (P , 0.01); and 2) a more proxi- cant results save one locus: D18S51 (P = 0.0007), but mal interval spanned by D21S1436 and D21S65 absent multilocus analysis the significance of this (P = 0.03–0.0003).