Susceptibility loci for bipolar disorder: overlap with inherited vulnerability to schizophrenia

Susceptibility Loci for Bipolar Disorder: Overlap with Inherited Vulnerability to Schizophrenia Wade H. Berrettini Genetic epidemiological studies reveal that relatives of bipolar probands are at increased risk for recurrent unipolar, bipolar, and schizoaffective disorders, whereas relatives of probands with schizophrenia are at increased risk for schizophrenia, schizoaffective, and recurrent unipolar disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed bipolar susceptibility loci for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11–13, and Xq26. Studies of schizophrenia kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11–13, both of which are implicated in susceptibility to bipolar disorder. Similarly, confirmed schizophrenia vulnerability loci have been mapped, too, for 6p24, 8p, and 13q32. Strong statistical evidence for a 13q32 bipolar susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two groups of disorders may not be as distinct as current nosology suggests. Biol Psychiatry 2000;47:245–251 © 2000 Society of Biological Psychiatry Key Words: Bipolar disorder, schizophrenia, genetic susceptibility, genetic linkage

Introduction

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istorically, schizophrenia (SZ) and bipolar (BP) disorder have been considered as nonoverlapping nosologic entities, with distinctive clinical characteristics, unique treatment regimens, and separate (albeit unknown) etiologies. A review of genetic epidemiology and recent molecular linkage studies, however, reveals a surprising degree of concordance for SZ genetics and BP genetics. This concordance raises the hypothesis that these two diagnostic categories may share some genetic susceptibility factors. As susceptibility genes are identified, this hypothesis can be tested.

From the Department of Psychiatry and the Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia. Address reprint requests to Wade H. Berrettini, Department of Psychiatry and the Center for Neurobiology and Behavior, 415 Curie Boulevard, Room 111, University of Pennsylvania, Philadelphia, PA 19107. Received June 3, 1999; revised July 28, 1999; accepted July 30, 1999.

© 2000 Society of Biological Psychiatry

Genetic Epidemiology of Bipolar Disorders Twin, family, and adoption studies indicate the existence of genetic predisposition for BP disorder. Concordance for BP disorder among monozygotic (MZ) twins is ⬃65%, whereas concordance for dizygotic twins is ⬃14%. The heritability of BP illness may be as high as 80%. In BP twin studies (Kendler et al 1992, 1993; McGuffin et al 1996), conducted with operationalized diagnostic criteria, validated semistructured interviews, and blinded assessments, the observations reported in earlier investigations are confirmed (for review see Berrettini 1998). One observation (with treatment implications) concerns polarity for concordant twins. Among MZ twin pairs concordant for mood disorder, when one twin has a BP diagnosis, recurrent unipolar (RUP) illness is present among 20% of the ill co-twins (Bertelsen et al 1977; Allen et al 1974). This observation is consistent with the hypothesis that BP and RUP disorders share some genetic susceptibility. If BP and RUP syndromes share common genetic vulnerability factors, then perhaps lithium should be used more frequently for prophylaxis of recurrent RUP illness (Souza and Goodwin 1991), especially when the person with RUP has BP first-degree relatives. Several mood disorders are found among the firstdegree relatives of BP probands: BPI, BPII with major depression (hypomania and recurrent UP illness in the same person), schizoaffective (SA) disorders, and RUP illness (Angst et al 1980; Baron et al 1983; Gershon et al 1982; Heltzer and Winokur 1974; James and Chapman 1975; Johnson and Leeman 1977; Maier et al 1993; Weissman et al 1984; Winokur et al 1982, 1995). The relative risk for BP disorder is ⬃10. Two family studies of SZ have reported increased risk for SA disorders and RUP illness in the first-degree relatives of individuals with SZ (Gershon et al 1988; Maier et al 1993). Thus, SA and RUP diagnoses are increased among the first-degree relatives of BP probands and also among the first-degree relatives of SZ probands. The diagnostic overlap in disorders affecting relatives of individuals with either BP or SZ disorders suggest some overlap in susceptibility, but no family studies have reported increased risk for BP disorder among the first0006-3223/00/$20.00 PII S0006-3223(99)00226-7

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degree relatives of SZ probands. Similarly, no family studies report increased risk for SZ among first-degree relatives of BP probands. Thus, these family studies are consistent with some partial overlap in susceptibility for BP and SZ disorders. Partial overlap between BP disorder and SZ is supported by a latent class analysis of clinical characteristics of mood disorders and SZ (Kendler et al 1998). In this regard, Crow (1990) has suggested a continuum model of psychosis, as opposed to the dichotomous structure first suggested by Kraepelin, who wrote later in life, “It is becoming increasingly clear that we cannot distinguish satisfactorily between these two illnesses, and this brings home the suspicion that our formulation of the problem may be incorrect” (Kraepelin, 1920).

A General Comment on Molecular Linkage Studies In genetic linkage studies of complex traits, validity is conferred only by demonstrating the underlying DNA sequence variants that explain the linkage statistics or through independent confirmation of the original linkage report in a second group of pedigrees. Statistical guidelines for judging validity of linkage reports in complex disorders have been suggested (Lander and Schork 1994; Lander and Kruglyak 1995). These guidelines suggest thresholds for a report of “significant” linkage (lod score ⫽ ⬃3.6, or nominal p ⫽ ⬃.00002) and for confirmation (lod score ⫽ 1.2, or p ⫽ ⬃.01). These guidelines should limit false positives to less than 5%. It should be remembered that these guidelines refer to analysis of a single phenotypic definition (e.g., BPI and BPII disorders). If multiple (overlapping) phenotypes are analyzed, some limited statistical adjustments for multiple hypothesis testing may be necessary. For example, in BP linkage studies one may analyze three overlapping affection-status models (e.g., BPI only; BPI/SA; BPI, BPII, SA, and RUP). This does not constitute three independent tests of significance, because the affection-status models are overlapping; the exact adjustment is not clear. Similarly, these guidelines are for a single analytic approach (e.g., nonparametric allele sharing in relatives or parametric lod score methods), but when multiple analytic methods are used, some small statistical adjustment may be necessary to reflect multiple hypothesis testing. Many different statistical programs, however, test variations on the theme that there is excess allele sharing among affected relatives, so the exact statistical adjustment is not clear. An associated critical issue is the power of a confirmation study to detect the effect size described initially. Effect sizes are often expressed as the increased relative risk due to a specific genetic locus (Risch 1990). This

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increased relative risk refers to the ratio of a proband’s relative’s (e.g., sibling) risk of developing the disorder divided by the risk for the general population. For BP disorder, family studies suggest that the relative risk for siblings is increased by a factor of ⬃10 (see Gershon et al 1982, for example). Because BP disorder is almost certainly an oligogenic syndrome in which at least several loci contribute to the increased relative risk, locus-specific relative risk (the increased risk due to a single locus) is expected to be much less than the total relative risk. For complex traits, such as hypertension, diabetes, and BP disorder, loci that increase risk by factors greater than 2 are unusual. One such locus is near the human leukocyte antigen (HLA) locus for insulin-dependent diabetes mellitus (relative risk ⬃3 [Davies et al 1994]); another is the apolipoprotein-E locus in late onset Alzheimer’s disease (Corder et al 1993; Mayeux et al 1993; Tsai et al 1994). Substantial sample sizes are required to detect such loci of minor effect, which increase risk by a factor of 2. As Hauser and Boehnke (1997) have shown, ⬃400 affected sibling pairs are needed to have ⬎95% power to detect (lod ⬎ 3) loci that increase risk by a factor of 2, whereas 200 pairs are needed to have ⬎95% power to provide confirmation (p ⱕ 0.01) of a locus detected previously. A final issue involves the concept of sampling variation. Suarez et al (1994) modeled a disorder caused by six equally frequent loci. In their simulations, a larger sample size and more time were required to confirm a previously detected locus compared with requirements for detection of another of the six loci. This seems reasonable intuitively, because the first locus to be detected (among the six equally frequent loci) was somewhat overrepresented in the first sample, explaining its detection. These simulations indicate that nonreplications, where excellent power exists in the sample size, must be expected. These simulations also suggest that the effect size described in an initial report may be somewhat overestimated.

Overlap in Linkage Studies of BP Disorder and SZ Multiple molecular genetic linkage studies of BP disorder and SZ have yielded confirmed evidence (Lander and Kruglyak 1995) for susceptibility loci across the human genome. If there is partial overlap in susceptibility to SZ and BP disorders (as suggested by family studies), then some of the loci implicated in SZ should also be detectable in BP kindreds, and vice versa. This issue is examined below. For reasons of validity (Lander and Krugylak 1995), this review will be limited to those loci for which there are two independent reports of linkage, one with a p value ⬃10⫺4–10⫺5 and at least one other with p ⱕ .001 in either

Susceptibility to Bipolar Disorder/Schizophrenia

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Table 1. Linkage Results (p Values) for Bipolar Disorder and 18p11.2 DNA Markers Study Berrettini et al 1997 Stine et al 1995 Nothen et al 1999a Knowles et al 1998

D18S53 (2)

S37 (2)

.04 .02 .03 .001

.01 .0003 .005 .08

DNA marker (in cM) S453 (2) S40 (3) .06 UR .002 .50

.0046 .02 .005 UR

S45

MP

.002 ns UR .0003

0.00008 UR 0.0004 ns

MP, multipoint; UR, unreported. Studies of 18p11.2 markers are summarized, with the nominal p values presented for individual markers and for a multipoint analysis where available. Results are presented for a narrow phenotypic definition in which only BPI was affected (Knowles et al 1998; Nothen et al 1999) or for a broader definition (Berrettini et al 1997; Stine et al 1995), in which SA, BPII, and RUP diagnoses are considered affected. a Results for paternal kindreds.

SZ or BP disorder. Once a confirmed locus is established for either BP disorder or SZ, the question is asked: Is there a molecular linkage study of the other disorder that reports evidence (p ⱕ 0.001) for a susceptibility locus at that same position in the human genome?

18p11.2 Berrettini et al (1994, 1997) reported significant evidence for a BP susceptibility locus on chromosome 18 using affected sibling pair (ASP) and affected pedigree member (APM) methods (p ⫽ 10⫺4–10⫺5), obtained in 22 Caucasian kindreds of European ancestry. Independent confirmation of this finding was reported by Stine et al (1995) and others as noted in Table 1. Evidence for linkage appears to be more prominent in those families with paternally transmitted illness (Gershon et al 1996; Knowles et al 1998; Nothen et al 1999; Stine et al 1995). Table 1 summarizes nominal significance levels for statistical analysis of marker genotypes located in a ⬃10 cM (⬃107 base pairs of DNA) region of chromosome 18p11. If the locus described by Berrettini et al (1994, 1997) increases risk for BP disorder by a factor of ⬃2, simulations indicate that ⬃200 affected sibling pairs are required to have ⬎90% power to detect it (Hauser et al 1996) at a significance level (lod score ⬎ 1.2 or p ⬍ .01) adequate for confirmation (Lander and Kruglyak 1995). Bowen et al (1998), Coon et al (1996), De Bruyn et al (1996), Kalsi et al (1997), Kelsoe et al (1995), Maier et al (1995), McMahon et al (1997), and Pauls et al (1995) studied samples from European, Icelandic, and North American populations and found no evidence for confirmation of linkage on 18p, but these sample sizes did not exceed 100 affected sibling pairs in any one study. However, the 18p BP locus has not been confirmed in the National Institute of Mental Health (NIMH) Collaborative Study (DeteraWadleigh et al 1997) in which an adequate sample size was evaluated. Genetic Analysis Workshop 10 (Goldin et al 1997) allowed statistical geneticists to analyze data from Berrettini et al (1997), Kalsi et al (1997), Knowles et al (1998), and Stine et al (1995). Results of several different analyses

were consistent with the existence of a BP susceptibility gene. For example, Lin and Bale (1997) analyzed the entire data set of 382 affected sibling pairs (assuming BP, SA, and RUP as affected) using a nonparametric method. At D18S37, for 382 affected sibling pairs excess allele sharing (58%) was evident, with p ⫽ 2.8 ⫻ 10– 8. Thus, there is a confirmed BP susceptibility locus on chromosome 18p11.2. Schwab et al (1998) employed ⬃20 chromosome-18 markers in a linkage study of 59 multiplex German and Israeli SZ pedigrees, in which there were 24 SA disorder cases (two were BP). When these data were analyzed in two-point parametric methods, the maximum lod score was 3.1 at D18S53. A multipoint, nonparametric analysis revealed (lod score ⫽ 2.9, p ⫽ .002) at D18S53. DeLisi et al (1995), in an independent study of multiplex SZ kindreds, reported p ⫽ .02 for an ASP analysis at D18S53. The 18p11 region may contain a gene that increases risk for psychotic disorders of varying syndromal form, consistent with genetic epidemiology and with some continuum models of psychosis (Crow 1990). The SZ kindreds studied for 18p11 linkage by Schwab et al (1998) are not nosologically or genetically distinct from other multiplex SZ kindreds. For example, these kindreds show linkage to chromosome 6p (Schwab et al 1995), as reported in other series of multiplex SZ kindreds (Moises et al 1995; Straub et al 1995). Nosologic misclassification does not explain the chromosome 18p11.2 linkage to SZ detected by Schwab et al (1998). Thus, the 18p11.2 region has a confirmed BP susceptibility locus, and there is a statistically impressive report of linkage at this locus in SZ.

13q32 Lin et al (1997) reported evidence for linkage of 13q32 markers (D13S122 and D13S128) in SZ, but the level of statistical significance was somewhat limited for an initial report (lod score ⫽ 2.58, p ⫽ ⬃.001). Subsequently, Blouin et al (1998) described statistically significant linkage to 13q32 markers (p ⫽ .00002 at D13S174) in 54 SZ kindreds. Thus, these two reports constitute a confirmed

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susceptibility locus for SZ, according to statistical guidelines (Lander and Kruglyak 1995). A third report has recently appeared (Brzustowicz et al 1999). DeteraWadleigh et al (1999) described linkage (p ⫽ .00003) to 13q32 markers (D13S1271 and D13S779) in 22 BP kindreds of European ancestry. Thus, the 13q32 region has a confirmed SZ susceptibility locus, and there is a statistically robust report of linkage at this locus in BP disorder.

22q11–13 Velocardiofacial syndrome (VCFS) is characterized by conotruncal cardiac defects, facial dysmorphology, cleft palate, and learning disabilities. Many VCFS patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including SZ, BP, and attention deficit hyperactivity disorder (Lachman et al 1996a; Papolos et al 1996; Pulver et al 1994b). The psychiatric manifestations of VCFS could be due to disruption of gene(s) within 22q11. Pulver et al (1994a) first described evidence for SZ linkage to 22q11–13. A meta-analysis of multiple data sets revealed some support for SZ linkage to this region (Gill et al 1996). Subsequently, weak evidence (p ⫽ .004 in a nonparametric test) for BP linkage to this same region was reported by Lachman et al (1996). Kelsoe et al (1998) reported a lod score of 3.8 at D22S278 in analysis of 20 multiplex BP kindreds, this being the most significant single finding in the region. Additional support for a BP susceptibility locus in this region comes from Edenberg et al (1997). Thus, for the 22q11–13 region, there are several reports of BP and SZ linkage. If the reports of Kelsoe et al (1998), Edenberg et al (1997), and Lachman et al (1996) are considered to represent a confirmed BP locus, there is substantial evidence for a SZ susceptibility locus in this general region.

Discussion Published linkage studies have defined a confirmed BP susceptibility locus on 18p11.2 in a region reported to have a linkage to SZ. Similarly, the 13q32 region has a confirmed SZ susceptibility locus, and there is a statistically impressive report of linkage at this locus in BP disorder. Linkage studies of BP disorder and SZ report positive lod scores in the 22q11 region, observations that are consistent with the varied nosologic presentation of psychosis in VCFS. If overlapping linkages in only one region of the genome had been reported for BP disorder and SZ, then this might be attributed to a false-positive observation. However, relatively convincing overlap (not the result of random statistical fluctuation) has been encountered in no

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fewer than three regions of the genome: 18p11.2, 13q32, and 22q11. This overlap is unlikely to be random and raises the possibility that BP disorder and SZ share some genetic susceptibility factors. This possibility is supported by family studies in these disorders, which show that first-degree relatives of BP or SZ probands are at increased risk for SA and RUP disorders. Confirmed BP susceptibility loci exist for regions of the genome where no SZ linkages have been reported. These regions include 18q22 (Freimer et al 1996; McInnes et al 1996; McMahon et al 1997; Stine et al 1995), where the Johns Hopkins group (McMahon et al 1997; Stine et al 1995) found evidence for a BP susceptibility gene among United States kindreds of European ancestry. McInnes et al (1996) described evidence for linkage in two extended Costa Rican kindreds for markers in 18q22. Blackwood et al (1996) reported on a single, large Scottish kindred that showed linkage (lod ⫽ 4.1 at D4S394) to 4p DNA markers, near the alpha-2c adrenergic and D5-dopaminergic receptor genes. They found weakly positive lod scores in several smaller kindreds of the same ethnic origins. They found no mutations in the dopamine receptor gene. Confirmation of the 4p locus has been noted by Nothen et al (1997), increased allele sharing was seen at D4S394 (p ⫽ .0009). Another confirmation was noted by Ewald et al (1998a), who described a lod score of 2 at D4S394. In a unique study, Ginns et al (1998) mapped to this region a locus for mental health, meaning absence of any psychiatric disorder. This requires additional investigation. Barden et al (1998) reported evidence for linkage of BP disorder to 12q24 markers in a Quebec population isolate of French ancestry. This was confirmed by Ewald et al (1998b), who described a LOD score of 3.37 in two Danish BP kindreds. Finally, Detera-Wadleigh et al (1999) reported modest evidence for linkage to 12q24 in BP kindreds from the eastern United States. Another confirmed BP susceptibility locus exists on 21q21 (Aita et al 1999; Detera-Wadleigh et al 1996, 1997; Gurling et al 1995; Kwok et al 1999; Straub et al 1994). Similarly, confirmed susceptibility loci exist in SZ for several loci where no BP linkages have been reported. These SZ susceptibility regions include 6p22– 4 (Levinson et al 1996; Moises et al 1995; Schwab et al 1995; Straub et al 1995) and 8p22– 4 (Blouin et al 1998; Kendler et al 1996; Levinson et al 1996; Pulver et al 1995). If this plethora of confirmed linkage regions in BP disorder and SZ seems overwhelming, it is instructive to recall that no fewer than 16 independent loci have been implicated in the cause of retinitis pigmentosa. At present, there are fewer than 16 confirmed loci for BP disorder and SZ, disorders that seem more complex and varied clinically than retinitis pigmentosa.

Susceptibility to Bipolar Disorder/Schizophrenia

Given the overlap in BP and SZ susceptibility loci, it is likely that some genes may predispose individuals to psychosis, with the clinical form of the disorder shaped by epistatic or additive effects of other loci, as well as environmental events. Advances in the genetics of BP disorder and SZ will result in redefinition of these two syndromes to multiple nosologic categories more closely reflecting their causes. It is a remarkable challenge to unravel complexity of this magnitude, but the common and devastating characteristics of these disorders demand that we meet this challenge so that new treatment opportunities can be developed. The preparation of this manuscript was supported in part by a Distinguished Investigator Award to W.H. Berrettini by the National Alliance for Research on Schizophrenia and Depression (NARSAD) and by NIMH Grant No. MH59533. The author thanks Sevilla Detera-Wadleigh for helpful discussions. Aspects of this work were presented at the Janssen CNS Summit on Psychiatric Genetics, February 9, 1999, Tempe, Arizona.

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