Patterns Fam 1998

7/28/2019 Patterns Fam 1998

1/8

Patterns of Parental Transmission and FamilialAggregation Models in Bipolar Affective Disorder

Maria Grigoroiu-Serbanescu,1* Maria Martinez,2 Markus M. Nothen,3 Peter Propping,3

Stefan Milea,4 Radu Mihailescu,1 and Elvira Marinescu1

1Psychiatric Research Laboratory, Marinescu Psychiatric Hospital, Bucharest, Romania2INSERM, Unit 358, Paris, France3Institute of Human Genetics, Bonn, Germany4Medical University, Bucharest, Romania

Two recent studies [McMahon et al., 1995:Am J Hum Genet 56:12771286; Gershon etal., 1996: Am J Med Genet (Neuropsychiatr

Genet) 67:202207] reported an excess of ma-ternal transmission in bipolar affective dis-order in multiply affected families. In asample of 130 families ascertained througha bipolar proband without regard to psychi-atric family history we analysed the fre-quency of maternal (MAT) and paternal(PAT) transmissions, the morbid risk (MR)in relatives of transmitting mothers and fa-thers and the inheritance patterns in fami-lies with MAT vs. PAT transmission of thedisease. In the total sample of 130 familieswe identified 39 families where the diseasewas transmitted from the paternal side(PAT families) and 35 families where the dis-ease was transmitted from the maternalside (MAT families). Counting PAT and MATtransmissions in these unilineal families wefound nearly equal numbers for both trans-mission types under a narrow (BP: bipolardisorder, schizoaffective-bipolar type disor-der) and a broad definition (AFF: BP, recur-rent unipolar depression) of the phenotype.The MRs for narrow and broad phenotypeswere not significantly different in any typeof PAT relative in PAT families vs. MAT rela-tives in MAT families. However, in PATfamilies there were two times more affectedfemales than males with both disease mod-

els, while in MAT families there was no MRdifference by relatives sex. The transmis-sion of BP was compatible with the Mende-lian major gene model in PAT families andwith the multifactorial model in MAT fami-

lies. Extension of the relatives phenotypeled to borderline non-Mendelian major ef-fects in PAT families and reproduced the

multifactorial model in MAT families. Am. J.Med. Genet. (Neuropsychiatr. Genet.) 81:397404, 1998. 1998 Wiley-Liss, Inc.

KEY WORDS: manic-depressive illness; pa-ternal inheritance; maternalinheritance; morbid risk; seg-regation analysis

INTRODUCTION

Recent research reported an excess of maternaltransmission of bipolar affective disorder in families

with a high loading of the disease. Investigating asample of 31 multiply affected unilineal families ascer-tained through bipolar probands having at least twoaffected sibs, or one affected parent and one affectedsib, McMahon et al. [1995] reported a significantlyhigher than expected frequency of affected mothers, a2.3- to 2.8-fold increased risk for bipolar illness andother major affective disorders in maternal relativesand a significantly higher risk for bipolar illness inoffspring of affected mothers than in offspring of af-fected fathers. Moreover, in seven pedigrees no in-stances of apparent paternal transmission were discov-ered.

Gershon et al. [1996] also found an excess of mater-nal transmission in their series of unilineal bipolar

pedigrees selected under the condition of the existenceof at least six affected persons in the family [Berrettiniet al., 1991]. The effect was observed in pairs transmit-ting a more restricted phenotype including only bipolardisorder and schizoaffective disorder-manic type aswell as in pairs transmitting a more broad phenotypewhich included, besides the restricted phenotype, re-current unipolar depression.

Results from epidemiologic studies, however, do notlend strong support to the observation of a significantexcess of maternal transmission in bipolar illness. Forexample, Gershon et al. [1982] found that the morbid

Correspondence to: Dr. Maria Grigoroiu-Serbanescu, The Psy-chiatric Research Laboratory, The Gheorge Marinescu Psychi-atric Hospital, Sos. Berceni, 10, O.P. 8, R-75622 Bucharest, Ro-mania.

Received 26 August 1997; Revised 11 March 1998

American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:397404 (1998)

1998 Wiley-Liss, Inc.


2/8


3/8

tive disorder). Schizoaffective disorder, unipolar, andmanic type were not found in the sample.

We counted maternal (MAT) and paternal (PAT)transmissions of BP and any major affective disorderconsidering each transmitting parent only once regard-less of the number of affected offspring.

Selection and Definition of Paternal andMaternal Families

The total sample of 130 families, either unilineallyaffected or with sporadic cases, was examined for indi-viduals with affective or schizoaffective disorder amongthe probands relatives. Families were retained for thepresent analysis only if the probands father or motherwas himself/herself affected or had an affected sib orparent. Three families with affected individuals in bothparental lines were excluded from the sample of 130families discussed here. We identified 39 independentfamilies with unilineal PAT transmission of BP and 35independent families with unilineal MAT transmis-sion. A PAT or MAT family was defined according to

the parent who transmitted the disorder to the bipolarproband but in former generations of the pedigree MATtransmission was allowed within a PAT family and viceversa (see Fig. 1). The BP probands were sporadic casesin the remainder 56 independent families since no af-fective or schizoaffective disorder was reported by rela-tives on either parental side.

Statistical Methods

Computation of lifetime morbid risks. We com-puted the lifetime MR for BP and for any major affec-tive disorder in PAT relatives of the probands in PATfamilies and in MAT relatives of the probands in MATfamilies, respectively, using the SURVIVAL procedure

of the SPSS software.Segregation analysis method. We have exam-

ined the homogeneity/heterogeneity in the familialtransmission of the disease according to the gender ofthe probands transmitting parent, by performing seg-regation analysis of the unilineal bipolar families, un-der narrow (N 51 pedigrees) and broad definition (N

74 pedigrees) of the affected phenotype in relatives

of the bipolar probands. The definition of the affectedphenotypes was as described above.

Segregation analysis was conducted under the uni-fied model [Lalouel et al., 1983] which incorporates thethree transmission probabilities defined by Elston andStewart [1971] into the mixed model [Morton and Ma-cLean, 1974]. The model allows for both major locus

and additive polygenic components of transmission ofthe trait. In this model, an autosomal diallelic locuswith alleles A and a is assumed to be in Hardy-Weinberg equilibrium. The parameters of the modelinclude: q, the frequency of the susceptibility allele A; t,the distance in standard deviation units on the liabilityscale between the two homozygous means; d, the rela-tive displacement of the heterozygous mean; h, the pro-portion of the total phenotypic variance attributable tothe polygenic component; tAAA, the probability that anindividual with AA genotype transmits the A allele;tAaA the probability that an individual with Aa geno-type transmits the A allele; taaA the probability thatan individual with aa genotype transmits the A allele.

Analyses were performed incorporating age-specific

liability classes. Four liability classes were considered:liability classes 1, 2, and 3 corresponded to individualsaged between 13 and 19, between 20 and 29, and be-tween 30 and 39, respectively. Individuals of age 40and over were assigned to liability class 4. Individualsunder the age of 12 with a negligible morbid risk wereremoved from the sample since none was affected. Forthe narrow diagnostic scheme females and males wereassumed to have the same morbid risk (N 51 pedi-grees; 27 PAT and 24 MAT pedigrees). For the broaddiagnostic scheme (N 74 pedigrees; 39 PAT and 35MAT pedigrees), analyses were conducted assumingdifferent morbid risks for males and females: four age-intervals, defined as above, were considered for eachgender, leading to the specification of eight liabilityclasses. Values for each liability class were derived foreach diagnostic scheme from population prevalences[Botezat et al., 1994], so that the lifetime prevalencewas equal to 0.8% under the narrow diagnostic scheme,and under the broad diagnostic scheme it was equal to3% and 5% for males and females, respectively. Foreach proband, the probability of ascertainment, pi, wasset to 0.001, approximating single selection.

The unilineal bipolar pedigrees were analysed usingthe POINTER strategy, as developed by Lalouel andMorton [1981]. These pedigrees were thus broken into195 (broad diagnostic) or 133 (narrow diagnostic)nuclear families, introducing pointers. Each pedigreewas partitioned into three components: nuclear fami-

lies with the proband as a child (PCF) (incomplete se-lection, pi 0.001); nuclear families with the probandas a parent (PPF) (complete selection); and nuclearfamilies including the probands father or the pro-bands mother as a child (PFF). Thus, when the af-fected individual was found in the probands fathers(or mothers) sibship, the ascertainment scheme ap-proximates a truncate selection, with a correspondingprobability of ascertainment equal to 1 (+ pointer whois the proband). Otherwise the affected relative is aparent of the probands father (or mother) and the se-lection is complete (plus pointer who is the proband).

Fig. 1. Example of paternal (PAT) and maternal (MAT) transmissionwithin a PAT family. BP I, bipolar I disorder; UP, recurrent unipolar de-pression.

Parental Transmission Patterns in Bipolar Disorder 399


4/8

Parameters of the model were estimated by maximiz-ing the likelihood of the offsprings phenotypes condi-tional either on the parents phenotypes for PCF andPPF families or on the parents and pointers pheno-types for PFF families. Subhypotheses of the full modelwere tested using the likelihood ratio criterion. Evi-dence for a major gene effect under the mixed model isobtained via a likelihood ratio test comparing themixed model to the multifactorial model. Segregationof a major gene is then asserted by testing the nullhypothesis of Mendelian transmission of this majorgene against the general transmission probabilitymodel.

Homogeneity tests were based on an a priori subdi-vision of the sample. The pedigrees were separated intothose showing a paternal transmission of illness (PATpedigrees) and those showing a maternal transmissionof illness (MAT pedigrees). Homogeneity tests betweenPAT and MAT subsets are done by calculating the dif-ference between the maximum likelihood of the overalldata (PAT+MAT) and the summed maximum likeli-hoods over the two subsets; twice this difference can becompared to a chi-square with degrees of freedom equalto the number of estimated parameters in the subsets.All computations were done with the computer pro-gram POINTER [Lalouel and Yee, 1980].

RESULTS

Paternal and Maternal Transmissions

Selecting families for unilineal inheritance resultedin a similar number of families with PAT and MATtransmission (39 PAT and 35 MAT). The number ofaffected mothers vs. affected fathers was 8 (6.2%) vs. 9(6.2%) for BP and 19 (14.6%) vs. 17 (13.0%) for anymajor affective disorder, respectively.

Counting the presence of PAT and MAT transmis-sions in the sample of 74 unilineal families revealed 28PAT and 29 MAT transmissions of the type BP-BP and40 PAT and 42 MAT transmissions of the type AFF-AFF (Table I).

Morbid Risk to Relatives

The MR for BP in first plus second degree paternalrelatives of BP probands in PAT families was not dif-ferent from the MR in first plus second degree mater-nal relatives in MAT families, although a slight ten-dency to more affected females was observed in PATfamilies and more affected males in MAT families(Table II). Since the computation of the MR in offspringdepends on the parents phenotype, probands mothersin MAT families and probands fathers in PAT familieswere excluded from computations. We also excludedprobands wife/husband, all maternal relatives in PAT

families and all paternal relatives in MAT families;probands children were excluded because some ofthem were below the risk age, and young probands hadno children; thus a potential bias source was removed.

The MR for any major affective disorder (Table III)computed in the same way as for BP did not differen-tiate the total group of paternal relatives in PAT fami-lies from the total group of maternal relatives in MATfamilies, but for paternal female relatives in PAT fami-lies the MR was two times higher than for male rela-tives (P .02 for the Lee-Desu statistic, DF 1), whilein MAT families there was no difference by relativessex.

We also compared the MRs in PAT and MAT familiestaking the probands parents as probands (Table IV).This time the MRs for BP and for any affective disorderwere computed only in first degree relatives of pro-bands parents since psychopathological informationabout their second degree relatives was not available.

The MR for BP and for any affective disorder in rela-tives of probands fathers in PAT families was not dif-ferent from the MR for BP and for any affective disor-der in relatives of probands mothers in MAT families.In PAT families, however, there was a two times higherMR in females than in males both for BP (P .003)and for any affective disorder (P .0004), while inMAT families male and female relatives were equallyaffected both with BP and any major affective disorder.

Because the first degree relatives of the bipolar pro-bands parents have passed through a longer period ofrisk than first degree relatives of bipolar probands, wealso computed the MR for BP and for any major affec-tive disorder in offspring of affected fathers and moth-ers. The risk was not significantly different in offspringof affected fathers vs. offspring of affected mothers nei-ther for BP (48.4% vs. 37.2%; P .87), nor for any ma-jor affective disorder (54.0% vs. 43.3%) (P .93).

A next step was to look at the structure of the MR forBP in first degree relatives of all transmitting fathersand mothers. As shown in Table V, there is only one

TABLE I. Paternal and Maternal Transmissions in Paternal vs. Maternal Families

BP-BP transmission AFF-AFF transmission

Paternalfamilies

Maternalfamilies Total

Paternalfamilies

Maternalfamilies Total

Paternal transmissions 27 1 28 39 1 40Maternal transmissions 5 24 29 5 37 42

TABLE II. Morbid Risk for BP Disorder in Paternal/Maternal

First and Second Degree Relatives of BP Probands in Paternalvs. Maternal Families

Paternalfamilies

Maternalfamilies

All first and second 11.5% 9.98%degree relatives (21/212) (18/212)

Male relatives 9.8%a 11.72%a

(9/111) (11/103)Female relatives 13.4%a 8.16%a

(12/101) (7/109)

aNo significant difference between male and female relatives either withinpaternal or maternal families.

400 Grigoroiu-Serbanescu et al.


5/8

significant difference between transmitting fathersand mothers, i.e., transmitting fathers have more af-fected daughters than transmitting mothers (P .04).Moreover, the MR for BP is significantly higher indaughters than in sons and in mothers than in fathersof transmitting fathers. Transmitting mothers show

only a trend to more affected brothers than sisters (P.08).

Segregation Analysis

Narrow definition of affected phenotype in rela-tives. a) Results of the segregation analysis under thenarrow definition are shown in Table VI. When theaffected phenotype of probands relatives is narrowlydefined, there is a high familial correlation in thetransmission of BP in PAT families (2 for sporadic/multifactorial model 13.26, DF 1, P < .0001). Theheritability H was .44. Absence of parent-offspringtransmission of the disease was rejected (2 for parent-offspring transmission/ general monogenic model was6.35, df 2, P


6/8

fects was rejected, but the additive and the recessivemodels were not rejected.

b) At the level of heterogeneity tests there was nosignificant difference between PAT and MAT families.

Broad definition of affected phenotype in rela-tives. a) The extension of the phenotype in probandsrelatives to any major affective disorders resulted alsoin a high familial correlation with an H value of .36 inPAT families (2 for sporadic/multifactorial model15.70, DF 1, P


7/8


8/8

ACKNOWLEDGMENTS

Dr. M. Grigoroiu-Serbanescu was a fellow of the Al-exander von Humboldt-Foundation (Bonn, Germany)at The Institute of Human Genetics of Bonn in theacademic year 1996/1997. First author is indebted toDrs. L. Giurgiuca, G. Marian, C. Constantinescu (Gh.Marinescu Psychiatric Hospital, Bucharest) for their

help in recruiting and diagnosing the patients.

REFERENCES

America n Psychi atric Associ ation (1997) : Diagnos tic and Statis ticalManual of Mental Disorders (3rd Ed., revised) (DSM-III-R). Washing-ton, DC: APA.

Arlen Price R, Kidd KK, Pauls DL, Gershon E.S, Prusoff BA, WeissmanMM, Goldin LR (1985 Multiple threshold models for the affective dis-orders): The Yale-NIHM collaborative family study. J Psychiat Res19:533546.

Berrettini WH, Goldin RL, Martinez MM, Maxwell ME, Smith AL, GuroffJJ, Kazuba DM, Nurnberger JI, Hamovit J, Simmons-Alling S, Muni-ecD, Choi H, York C, Robb AS, Gershon ES (1991): A bipolar pedigreeseries for genomic mapping of disease genes: Diagnostic and analyticconsiderations. Psychiatr Genet 2:125160.

Blangero J, Elston RC (1989): Familial analysis of bipolar affective disor-

der using logistic models. Genet Epidemiol 6:221227.Botezat L. (1994): Epidemiology of the DSM-III-R psychiatric disorders in

the general population of Romania. Work report of The Statistical Cen-ter of Health Ministry.

Elston RC, Stewart J (1971): A general model for the genetic analysis ofpedigree data. Hum Hered 21:523542.

Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W,Targum SD, Nurnberger JI, Goldin LR, Bunney WE (1982): A familystudy of schizoaffective, bipolar I, bipolar II, unipolar, and normal con-trol probands. Arch Gen Psychiatry 39:11571167.

Gershon ES, Badner JA, Detera-Wadley SD, Ferraro TN, Berrettini WH

(1996): Maternal inheritance and chromosome 18 allele sharing in uni-lineal bipolar illness pedigrees. Am J Med Genet (NeuropsychiatrGenet) 67:202207.

Lalouel JM, Yee S (1980): POINTER: A computer program for complexsegregation analysis with pointers. Technical report (Population Ge-netics Laboratory, University of Hawai, Honolulu.

Lalouel JM, Morton NE (1981): Complex segregation analysis with point-ers. Hum Hered 31:312321.

Lalouel JM, Rao DC, Morton NE, Elston RC (1983). A unified model forcomplex segregation analysis. Am J Hum Genet 35:816826.

McMahon FJ, Colin Stine O, Meyers DA, Simpson SG, DePaulo JR (1995):Patterns of maternal transmission in bipolar affective disorder. Am JHum Genet 56:12771286.

Morton NE, MacLean CJ (1974):Analysis of familial resemblance. III.Complex segregation analysis of quantitative traits. Am J Hum Genet26:318330.

NIMH-Molecular Genetics Initiative (1991): Family Interview for GeneticStudies.

NIMH-Molecular Genetics Initiative (1991): Diagnostic Interview for Ge-netic Studies.

Rice J, Reich T, Andreasen NC, Endicott J, Van Eerdewegh M, Fishman R,Hirschfeld RMA, Klerman GL (1987): The familial transmission of bi-polar illness. Arch Gen Psychiatry 44:441447.

Serbanescu-Grigoroiu M, Nothen MM, Propping P, Poustka F, MagureanuS, Vasilescu R, Marinescu E, Ardelean V (1995): Clinical evidence of

genomic imprinting in bipolar I disorder. Acta Psychiat Scand 92:365370.

Serbanescu-Grigoroiu M, Wickramaratne P, Hodge S, Milea S, MihailescuR (1997): Genomic imprinting and anticipation in the bipolar I illness.Br J Psychiatry 170:162166.

Spence MA, Flodman PL, Sadovnick AD, Bailey-Wilson JE, Ameli H,Remick RA (1995): Bipolar disorder: evidence for a major locus. Am JMed Genet (Neuropsychiatr Genet) 60:370376.

Spitzer RL, Williams JBW, Gibbon M (1987): Structured Clinical Interviewfor DSM-III-R Personality Disorders (SCID-II). New York: New YorkState Psychiatric Institute.

404 Grigoroiu-Serbanescu et al.

Patterns Fam 1998

Documents

Transcript of Patterns Fam 1998