J psychrar RET, Vol 26. Prmted I” Great Bntam

No

4, pp

271-271,

1992 (:

GENETICS

OF AFFECTIVE ENRICO

Institute

of Medlcal

GenetIcs,

Umverslty

0X22-3956/92 $5 CUJ + 00 1992 Pergamon Press Lid

DISORDERS

GANDINI

of Ferrara,

Via L Borsarl

46, 44100 Ferrara,

Italy

Summary-Studies of the mode of Inheritance of affective disorders have been revlewed The overall picture which emerges does not seem to mvolve speclflc modes of mherltance Lmkage studies based on the smgle gene hypothesis, support X-hnkage for a bipolar variant, as well as possible lmkage to chromosomes 6 and 11 The more recent approach of hnkage studies usmg large numbers of RFLP markers scattered throughout the genome looks promlsmg, though it may stdl give rise to mlsmformatlon Several confoundmg factors have been suggested such as genetic and phenotyplc heterogeneity, as well as the lack of well defmed dlagnostlc crlterla

Introductron many case reports m the pre-Mendehan era, genetic studies m affective dtsorders were performed accordmg to the phenotyptc-btometrtc approach It has been clearly established that genetic varrabrhty plays a major role m causing these condntons Affective disorders represent a prevalent (1-2070) and major group of rllnesses or episodes characterized by drsphorla which are associated with somatic symptoms They may have a manic-depressive (bipolar) or purely depressive (umpolar) course. The role of genetic factors is mdrcated by family studies, concordance m monozygotrc and dtzygottc twins and correlation between adopted persons and then blologrcal relatives Therefore the risk of a mayor affective disorder increases with the proportion of genes shared with an affectively 111proband and is higher m relatives than m the general populatron. A wide range of estimates has been given by different surveys and empnxal rusks important m genetic counselhng have been developed Harper (1988) reports the following genetic risks for relatives of an affected proband (Table 1): rf the proband’s age at onset is > 40 years, the risk should be increased by about 20%, and reduced by 10% tf the age of onset 1s 3 7

4

1

4 3

L

G6PD HEMA

Figure

Chromosome

I Figures

refer to the number

of hnkage

studies

1 1

reported

In S V Faraone

et al

6

Smeraldl and coworkers (1978) first suggested HLA linkage of affective disorders usmg the affected Sib method The excess of HLA slmllarlty m affected slbshlps compared with discordant pairs was considered m favor of an HLA linkage with a major affective disorder

275

GENETICS OF AFFECTIVE DISORDERS

gene. It is interesting that stmtlar studies performed on siblings having three or more 111 members did not give evidence of hnkage. It appears that the effect of HLA is greater m unipolar than m bipolar disorders and more apparent in families with few affected members than in “high load” famihes (Stancer et al., 1988; Weitkamp, 1981). Lod score analysis was also performed with contrasting results. Overall, 4 out of 12 studies gave statistical evtdence m favor of linkage (Figure 2).

Lod +

score -

1

>3 ?

7

6 Fzgure 2 Figures

Chromosome

to the number

of hnkage

studies

reported

m S V Faraone

et al

11

Egeland et al (1987) described linkage of a dominant gene predrsposmg to mamacdepressive illness to RFLP polymorphism, on the tip of chromosome 11 (see Figure 3). The presumed locus was closely lurked to HRAS-I and INS m the Old Order Amish of Lancaster County. The tyrosme hydroxylase gene, which maps m thts area, was suggested as a candidate gene because it catalyzes an important step m the dopamme syntheses pathway. Other groups have failed to fmd evidence of hnkage to 1 lp markers HQAS.1 and INS (Gill, McKean, & Humphries, 1988). Gmns (1992) discusses more widely the development of Older Amish linkage studres The question is why the results of neither genetic models nor linkage studies cannot be repeated.

276

E

GANDINI

Lod +

score -

>3 7

r

HRASl

il FSHB ‘P2

TYR PGR 2 ETSl APOLPl

Figure

3 Figures

refer to the number

ot linkage

-r

studies

APOAI APOC3 APOA4

L

reported

III S V Faraone

et al

In some families apparently the SML model IS effective, m others the MFP model fits the data better and m yet others no model explains disease inheritance And on the same line, m some families a maJor gene appears to segregate with chromosome 6; m others with the X chromosome; m others with the tip of chromosome 11 and finally m others with none of these 1oc1 The same factors that are comphcatmg genetic lmkage analysis, possibly affect the genetic model study Three mam types of errors should be mentioned (a) according to Claramello and Claramello (1991), the mam problem 1s the lack of “objective diagnostic criteria”, (b) standardized criteria that Kldd and Kennedy (1989) mentioned a few years ago as “the revolution m psychiatry” have improved, but accurate diagnosis 1s problematic, because of the lack of well defined blologlcal markers, and (c) heterogeneity may be the most important source of “error”. Commenting on this topic McKuslch (1990) states that “It 1s a case of mtersectlon between heterogeneity and multlfactorlal model” Other possible errors may derive from cases completely due to environmental effects If the frequency of phenocoples 1s high, the impact on the genetlc hypothesis may be substantial No defmltlve conclusions can be drawn from all the work done Nevertheless psychiatric geneticists remam cautiously optlmlstlc and pressure 1s created to find new strategies to investigate the disease The outlook of the linkage studies 1s promlsmg Progress of the “genome prolect” will lead to the ldentlflcatlon of large numbers of polymorphic sites that can be used as markers m RFLP linkage studies with the affective disorders genes m large pedigrees

GENETICS OF AFFECTIVE DISORDERS

277

As clearly stated by Lander (1988), the future approach to linkage studies will be made using large standard batteries of hundreds of RFLPs markers distributed throughout the genome. Any interval showing evidence of linkage will be studied with a high density of RFLPs. Full mformatlon from the pedigrees and an increase of the lod score is expected The future IS already here together with the limitations of this type of approach On the other hand as Lander (1988) suggests, if the trait is more complex than we assume, if for example 100 genes are involved, no linkage will be detected But a negative result will prove that the disease 1s more complicated than assumed, and this also will be an answer. References Craramello, R D , & Claramello, A L (1991) Genetrcs of maJor psychtatrrc dtsorders AnnualRewew ofMedrcme, 42, 151-158 Egeland, J A , Gerhard, D S , Pauls, D L , Sussex, J N , Kldd, K K , Allen, C R , Hostetter, A M ,& Housman, D E (1987) Bipolar affective disorders hnked to DNA markers on Chromosome 11 Nature, 325, 783-787 Falconer, D S (1965) The mherltance of habthty to certam dtseases estimated from the incidence among relatives Annals of Human Genetrcs, 29, 51-76 Faraone, S V , Kremen, W S , & Twang, M T (1990) GenetIc transmtsston of maJor affecttve disorders quanntatlve models and hnkage analysrs Psychologrcal Bulletm, 108, 109-127 Gill, M , McKean, P , & Humphrles, P (1988) Lmkage analysrs of manic depression in an Irtsh family using HRAS-I and INS-DNA markers Journal of Medrcal Genetics, 25, 634-631 Harper, P (1988) Practrcal genetrc consellmg Wrrght, London Ktdd, K K , & Kennedy, J L (1989) The genettcs of affectwe disorders In L Wetterberg (Ed ), Genetrcs of neuropsychratrrc drseases (pp 191-198) MacMillan, London Lander, E S (1988) Mappmg complex genetic traits In humans In K E Davies (Ed ), Genome analysts, a practrcal approach (pp 171-189) IRL, Oxford McKustck, V (1990) Mendelran rnhentance m man Johns Hopkms University Press, Balttmore Morton, N E , & MacLean, C (1974) Analysts of famrly resemblance III Complex segregation analysis of quantttatlve traus Amerrcan Journal of Human Genetrcs, 26, 489-509 Reich, T , Clayton, P J , & Wmokur, G (1969) Famrly hrstory studies V the genetics of mama Amerrcan Journal of Psychratncs, 125, 1358-1369 Smeraldl, E , Negro, F , Mehca, A M , & Scorza-Smeraldr, R (1978) HLA system and affective disorders a sibship genettc study Tcssue Antrgens, 12, 270-274 Stancer, H C , Wenkamp, L R , Persad, E , Flood, C , Jorna, T , Guttormsens, A , & Yagnow, R L (1988) Conftrmatlon of the relattonshtp of HLA (chromosome 6) genes to depresston and manic depression II The Ontario follow-up and analysis of 117 kmdreds Annals of Human Genetics, 52, 279-298 Weltkamp, L R (1981) HLA and disease predrctlon for HLA haplotype sharing in families Amerrcan Journal of Human Genetrcs, 33, 776-784

Genetics of affective disorders.

Studies of the mode of inheritance of affective disorders have been reviewed. The overall picture which emerges does not seem to involve specific mode...
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