Journal of Affectire Disorders, 26 ( 1992145-52 0 1992 Elsevier Science Publishers B.V. All rights reserved 01650327/92,PjO5.00
JAD 00924
We investigated the risk for substance abuse in the biological relatives of adoptees with affective illness, controlling for potential confounds, and additionally assessed risk by prGbands’ and relatives’ gender. Our sample consisted of 67 index adoptees with affective illness, matched control adoptees, and their biological and adoptive relatives. Both affective illness and substance abuse were more common in the biological relatives of affectively ii! adoptees than in controls’ relatives. Affective illness was more common than substance abuse among female index biological relatives, with the opposite pattern observed among male relatives.
Key words: Qepression;
Alcohol abuse; Substance
In 1986, Wender and his colleagues reported the results of an adoption study of affective disorders which they had conducted in Denmark (Wender et al., 1986). The strategy employed was that of determining the prevalence and types of psychiatric disorders in the biological and adoptive relatives of adults with affective disorders who had been adopted at an early age (the index cases), and in matched adoptees without a record of psychiatric disordars (the control cases). If
Correspondence to: Loring J. Ingraham, Room Building 10, NIMH, Bethesda, MD 20892, USA.
4Cll0,
abuse; Genetics
genetic factors contribute ao the transmission of mood disorders, one would expect to find an increased prevalence of such disorders in the biological relatives of the index cases as compared to the biological relatives of the controls. If familial psychological or other non-genetic factors play a role in the transmission of mood disorders, one would expect to find an increased prevalence of such disorders in the adoptive relatives of the index cases as compared to those of the controls. What was found - a significant increase of mood disorders and suicide among the biological relatives of the index cases as compared to the biological relatives of the controls, and no increase in mood disorders or suicide among adoptive relatives of the index cases as
compared to the adoptive relatives of controls was supportive of genetic factors in the transmission of these disorders. An additional finding was an increased frequency of alcohol and other drug abuse (subsequently referred to as substance abuse) in the biological relatives of the index cases compared to the biological relatives of the controls. In that report, the authors suggested that the observed increase in substance abuse in the biological relatives of the index cases might be an artifact of the methods employed. Diagnoses of the relatives were based on records of psychiatric hospitalization(s). The increased rate of hospitalization among the biological relatives of the index cases might have led to an increased rate of ascertainment of substance abuse in these relatives - individuals whose substance abuse was incidental and would not in itself have resulted in psychiatric hospitahzation. Another potential confound could arise if some of the affectively ill probands also had evidence of substance abuse. IIf so, an excess of substance abuse among probands’ bioIogica! relatives might reflect the operation of a genetic factor related onIy to substance abuse, and not affective illness. We have recently reviewed the literature on the relationship between substance. abuse and affective illness and have re-examined our own data to see if they could help clarify the observation of excess substance abuse in the biological reIativcs of adopters with affective illness. Over the past twenty five years a considerable and conflicting literature has developed on the genetics of affective disorders and its relations to alcoholism. Winokur’s early identification of an association between alcoholism and affective disorder (Winokur and Pitts, 1965; Pitts and Winokur, 1966) stimulated closer investigation of the rclationship between these disorders and initiated work aimed at determining whether the co-occurrence of affective disorder and Jcoholism in families represented alternate expression of the same liability. In one approach, Goodwin and his colleagues (1973, 1977a, 1977b) conducted a series of studies of adopted-away children of an altoholic parent. An increase of depression was not seen in the adopted away daughters of alcoholic fathers but was seen in the daughters of alco-
holics raised by their biologica! parents. The authors conclude that their studies neither demonstrate nor rule out the operation of a common genetic factor in akoholism and depression. Cloninger and colleagues reviewed this area in 1979 and concluded that there was a complex pattern of association among alcoholism, affective disorder, and other psychiatric disorders. in particular, these investigators noted that an increased frequency of heavy drinking, a precondition for alcoholism, may be observed in various psychiatric illnesses without necessarily implying that a putative gene for any of these disorders also plays a role in the development of alcohol abuse. Schuckit (1986) has also reviewed this area and concluded that alcoholism and affective disorder are independent diseases with some overtap in symptoms. Merikangas and GeIernter (19901 conducted another review and concluded that it was unlikely that alcoholism and depression have a common etiology. Conversely, Finn and his colleagues (1490) reported an increased risk for major affective disorder in non-alcoholic men (and their first and second degree relatives) with a muhigenerational family history of alcoholism, suggesting that alcoholism and depression may be cosegregating in these families. Active investigation in this area continues (Hodgkinson et al., 1991). Pickens and his colleagues (Pickens et al., 19911 suggest that genetic factors have only a modest effect on overall risk for alcohol abuse, but that there may be some forms of alcoholism which are moderately to highly heritable, Winokur and Coryell (1991) found an increased rate of alcoholism in the families of depressed women, (but not depressed men), and conclude that the ‘familial association between alcoholism and depression may be the result of either genetic or environmental factors or an interaction between the two’ (Winokur and Coryell, 1991, p. 184.1 Hn addition to investigating the effect of probands’ gender on the risk of illness in relatives suggested by Winokur and Coryeil’s report, it is essential to study the gender of affected relatives when investigating the relationship between affective disorder and substance abuse. Epidemiological studies indicate asymmetry in the liability
47
for affccltive disorder and substance abuse such that women arc more likely to have a diagnosis of an affective disorder and men are more likely to be identified as substance abusers (Weissman and Klerman, 1947; Weissman et al., 1984). Additional evidence suggestive of substance abuse or affective disorder as alternative expressions of a liability mediated by gender comes from the study of populations where intoxicants are not used, and therefore substance abuse does not occur. In
a study of the Amish, Egeland and I-Iostetter (1983) report similar rates of affective disorder in both men and women. In most previous studies of the relationship between affective illness and substance abuse or addiction, investigation of the independent contribution of genetic factors to the risk for substance abuse in the relatives of individuals with affective illness has been hampered by the commingling of genetic and non-genetic familial factors. Adoption designs can address this issue by separating post-natal family environ-
ment from parental genetic effects. Goodwin’s studies (1973, I977a,b) focused on a high-risk approach, following the adopted away offspring of an alcoholic parent. In this report, we have used the adoptee family strategy, which focuses on the biological relatives of affected adoptees here probands with mood disorders, and matched control adoptees free from affective disorder and their biological relatives. The strength of the adoption study strategy lies in its ability to separate the effects of genetic influences on the development of psychopathology from the effects of post-natal familial environmental influences. In psychiatric illnesses and behavioral disorders, this separation is particularly important as the similarities observed among family members may well be learned behaviors rather than the result of heritable genetic factors. MethOdS
The adoption
study methodology
has been previously described in detail elsewhere (Kety et
al., 1968). The analyses presented in this paper are based on the data previously reported by Wender and his colleagues (1986?, which have here been analyzed to address potential confounds in the diagnosis of substance abuse and to
examine the effect of probands’ and relatives’ gender on liability to illness. In brief, the index and contrul /adoptees were selected from the entire pool of 14,500 adoptees born in Denmark between I924 and I947 and who had been placed in the homes of non-relatives. The names of these adoptees were cross-indexed with a central register of psychiatrically hospitalized Gersons (the Institute for Human Genetics) and abstracts of their hospital records obtained and examined. Those who received a
consensus diagnosis of unipolar (N = 27) or bipolar (N = 10) major affective disorder, neurotic depression (N = 21; equivalent to IX&I-III dysthyrnic disorder), or affect reaction (N = 13; a Danish diagnostic category reflecting histrionic, panicky behavior or an impulsive suicide attempt) were selected from this pool as index probands; there were 48 fe.male and 23 male adoptees thus selected. For each index proband, a control proband was selected. Control probands were selected from the Danish adoption records as the closest individual in the enumerated adoption records (and thus adopted near the time of the index proband’s adoption) without a record of a psychiatric hospitalization, substance abuse, or attempted or completed suicide, and who was matched with the index proband by the criteria of gender, age, time spent with biological mother, age at transfer to adoptive home, and socioeconomic class of adopting parents. The biological and adoptive relatives of the index and control adoptees were identified through the use of the extensive Danish population registers, and records of psychiatric hospitalization. The hospital charts were abstracted and translated into English, and any identifying information that might indicate the biological/adoptive or index/control nature of the individuals removed. DSM-III diagnoses based on these records were made independently by two of the authors (Wender et al. 1986: PW, SK) and disagreements resolved by consensus. After final diagnoses were made, a research assistant de-
coded the identifying numbers and sorted the records into the appropriate biological/adoptive and index/control groups. Relatives who had died or emigrated before
reaching the age of 15 were excluded from the sample, leaving 194 male and 193 female biological index relatives and 191 male and 153 female biological control relatives.
TABLE
1
Affective disorder and substance abuse in relatives of index and control prcbands free from substance abuse * Biological
Relatives, No. (%I
As previously reported (Wender et al., 1986), a significantly greater incidence of affective disorders (Fisher exact one-tail P = 0.034) and substance abuse (Fisher exact one-tail P = 0.013) was observed in thg: biological relatives of the index cases as compared to the biological relatives of controls. There were no significant differences among the adoptive relatives. In order to test whether the greater number of diagnoses of substance abuse among index bioiogical relatives was an artifact due to the incidental observation of substance abuse in relatives hospitalized for other psychiatric diagnoses, we compared the risk for a diagnosis of substance abuse in index and control individuals who had a psychiatric hospitalization for other than substance abuse, As previously stated, psychiatric hospitalization was more common among biological index relatives than among the biological relatives qf controls, so that there was potentially a greater chance to observe evidence of substance abuse in these relatives than among control biological relatives who had fewer hospitalizations. There were 56 individuals among 386 bioiogicx ra:Iative~ and 31 individuals among 343 biological control relatives with a history of hospitaIization for a psychiatric disorder other than substance abuse (Fisher exact one-taiI P = 0.015). (There was one biological relative each in the index and control groups hospitalized with a diagnosis of substance abuse and with no other psy-
chiatric diagnosis, who have been excluded from this analysis of potential incidental observation of substance abuse.) 0f the S6 biological index relatives with a diagnosis, 20 (35.7%) also had a concomitant history of substance abuse, com-
paied with 6 09.4%) of 31 biological control relatives with substance abuse in addition to another psychiatric diagnosis (Fisher exact one-tail P = 0.087). Th e increased proportion of substance abuse observed among diagnosed biolagical index relatives makes it unlikely that the in-
Definite and uncertain Index
Control P
Substance Index
unipolar 19 (5.2) 8 (2.4) 0.03h
Adoptive ReMiVeS, No. (S-1 and bipolar disorders 3 (1.81 3 (1.9) 0.629
abuse and dependence 20 15.4)
Control
7 (2.1)
P
0.018
Total number of relrrtives 397 Index
169
328
159
Control
* There are 6 biological index relatives with both affective disorder and substance abuse who are inclued in both totals. The number of affected relatives in s-he index and control groups were compared via one-tailed Fisher’s exact probability tests.
crease in substance aDuse in the biological relatives of index probands is due to an artifact secondary to increased incidence of other dissrders. Another potential confound we wished to control was the presence of substance abuse in the affectively ill index probands; such co-morbidity might represent an independent risk of substance abuse in the probands’ biological relatives, independent of any risk represented by affective illness itself. Hf genetic contributions to substance abuse are different from those associated with affective disorders, one might obtain an increased risk for both disorders in the biological relatives of index cases with both an affective disorder and substance abuse. 0f the 71 index adoptees, 4 were also substance abusers, and these 4 index probands, along with thsir matched controls and their biological and adoptive relatives were eliminated from subsequent analyses. Table 1 presents the distribution of affective disorders and substance abuse in the relatives of
index probands free from substance abuse. The excess of both affective illness (Fisher exact onetail P = 0.046) and substance abuse (Fisher exact
one-tailP = 0.018) observed among bisbgical relatives of ill probands in the full sample He-
sents the distribution of affective
disorders and
substance abuse in the maEe and female biological and adoptive relatives of mafe and female index cases and controk, and indicaFes the percentage of affected relatives in each group. In every case for both affective tilness and substance abuse, and whether examined by gender of proband or relative, more index than control biological relatives were affected, As previously observed, adoptive relatives were at low risk for illness. Risk for affective disorder and substance
mains, supporting the finding of excess substance abwe among bislsgical relatives of affectively ill probands. As an exploratory analysis of the possible effects of gender on Biabihty for affective disorder and substance abuse, we examined the pmbands and relatives’ diagnoses by gender. In this exploratory andysis, cell sizes are smalI and geneealizability is consequently limited. Table 2 pre-
TABLE 2 Affective disorder and substance and relative *
abuse in relatives of index and control probands free from substance
Biological Relatives of: Male Probands No. I%) Definite and uncertain
Female Probands No. (%J
Relatives OF:
Male Probands No. (961
Female Probands No. C%‘c)
unipolar and bipolar disorders
Index Malerelatives Female relatives Control
Adoptive
abuse by gender of proband
Male relatives
Female relatives
2 0.3) b iP.CI
4 (3.3) 7 (5.9)
0 0
2 (3.6) 141.7)
1(1.6) 3 16.3)
2 Cl.71 2 (2.0)
0 1 (3.3)
0 2 (3.3)
5.2% of the male & female biological relatives of the male & female probands ti zre affected overall; 6.3% of M&F biological relatives of M probands 3.6% of MEF bioiogical relatives of F probands 3.3qc of M biological relatives of M&F probands 7.0% of F biological relatives of M&F probands Substance abuse and dependence Index Mak relatives Female relatives
5 (8.3) 2 (2.0)
7 CS.8) 6 IS .a!
0
l(1.8)
1 (3.4)
0
Control Male relatives Female relatives
3 (4.7) z CL11
2 (1.7) i(1.0)
0
2 (3.8) 0
5.4% of the male & female biological relatives of the male & female probands 5.5% of M&F biological relatives of M pmbands 5.4% of M&F biological relatives of F probands 6.6% of M biological relatives of M&F probands 3.3% of F biological relatives of M&F probands
i
(3.3)
were affected overall;
Number of relatives: Index Male Female
60 67
121 119
26 29
56 58
Control Male Female
64 48
118 98
25 36
53 51
* There are 2 male and 4 female biological index relatives with both affective disorder and substance both groups.
abuse whfi are inc!uded in
DeCinite and uncertain and bipolx diwrders
unip;kir
DtA’inite and uncertain unipolar and bipolar disorders & Substanw ;~buse and dependence SuMancc Chi-Square
~~tiusr and dependence \+ith 2df = h. 1-I: one-tail
4
9
Z
3
IO
3
P = (1,3X
abuse was similar b, wtn the relatives of male and female index probands. We observed a trend
for increased risk of affective illness in female biological index relatives compared with male bio!ogicaI index relatives (Fisher exact one-tail P = 0.089~. Table 3 presents the distribution of affective and substance abuse diagnoses in the male and female biological relatives of the index probands, and indicates an excess of affective disorder among female relatives and an excess of substance abuse among male relatives (Chi-Square. 2df = 5.14, P = 0.038L Controlling for potential ascertainment artifact due to differences in the number of male and female biological relatives with a diagnosis further highlights this asymmetry. Of the 23 male biological index relatives with a psychiatric hospitalization for a diagnosis other than substance abuse, 12 (52.2%) also had a history of substance abuse, compared with only 7 K?l.Y’ 1 of 32 female biological control relatives (Fisher exact one-tail P = 0.015).
The major finding of this report is an increased frequency of substance abuse in the bioIogicrll relatives of adoptties with a diagnosis of an affective disorder, even when selecting affectively ill probands free from substance abuse. Substance abuse is more frequently observed in male bioIogica1 relatives than female biological
relatives, and a converse pattern is observed in the risk for affective disorder. Some important limitations must be noted. Our assessment of substance abuse in the biological relatives of index probands was in all but one case in addition to another psychiatric diagnosis. This may limit the relevance of our findings for alcoholism or other drug addiction uncomplica ted by psychiatric comorbidity. However, the psychiatric diagnoses of the substance abusing biological relatives were distributed among a broad range of psychopathology from schizophronia to affective disorder to personality disorders, which argues against the likelihood that the substance abuse wt’ observed was a feature of a specific diagnosis (such as antisocial personality disorder) common to affected biological relatives. Our probands were selected on the basis of a psychiatric hospitalizaaiom for an affective disorder, and so our findings may be limited to more severe affective illness. However, by restricting our study to the relatives of individuals with a hospitalization for affective illness, we may have been able to study a more homogeneous group of probands than in studies of milder or mixed psychiatric disorders or in studies of alcoholic probands. If there is a common genetic liability for some affective illness and substance abust: which is mediated by gender, then we would expect to see these illnesses segregating by gender within the biological families of adoptees. In most of the families we studied no more than one biological relative was ill, and in only three of our families was there at least one diagnosis of affective illness or substance abuse in both a male and female relative. In this very small subsample of three families, affective illness was seen exclusively in female relatives and substance abuse was seen in both male and female relatives. Offsetting the potential limitations of our design and sample are some notable strengths. In particular, the adoption study design used here separates the effect of family environment from that of genetic liability. The use of control adoptees and their biological relatives permits the conclusion that the distribution of substance abuse observed reflects more than a general tendency for males to be more likely to be identified
51
as substance abusers, and that the observed increase is specific to the biological relatives of affectively ill probands. In conclusion, the present analysis provides evidence for a genetically transmitted liability for substance abuse as well as affective disorder among the biological relatives of ind: Aduals with a history of affective disorder. Furthermore, liability in relatives for affective disorder or substance abuse is related to gender such that female relatives of affectively ill individuals are at greater risk for affective illness than substance abuse, while male relatives have a greater risk for substance abuse.
We acknowledge with appreciation the collection and abstracting of Danish records by Drs. J. Ortmann and 1. Lunde.
Cloninger. C.R., Reich. T. and Wetzei. R. (19793 Aicoh~lism and affective disorders: familial associations and genetic models. In: D.W. Goodwin and C.K. Erickson (Eds.). Alcoholism and Affective Disorders: Clinical, Genetic and Biochemical Studies. SP Medical and Scientific Books. New York. EgGland. J.A. and Hostetter, A.M. (1983) Amish study. I: Affective disorders among the Amish, 1976-1980. Am. J. Psychiatry 140, 56-61. Finn, P.R.. Kleinman. I. and Pihi, R.O. (1990) The lifetime prevalence of psychopathology in men with muitigenerationai fdmiiy histories of alcoholism. J. Nerv. Ment. IX. 178,500-504. Goodwin, D.W., Schuisinger. F., Hermansen. L.. Guze, S.B. and Winokur. G. (1973) Alcohol problems in adoptees raised apart from alcoholic biological parents. Arch. Gen. Psychiatry 28, 238-43.
Goodwin, D.W., Schulsinger, F., Knop. J.. Mednick, S. and Guze, S.B. Cl977ab Alcoholism and depression in adoptedout daughters of alcoholics. Arch. Gen. Psychiatry 34, 75 l-5. Goodwin, D.W., Schulsinger, F., Knop, J., Mednick, S. and Guze, S.B. (1977b) Psychopathology IQ adopted and nonadopted daughters of alcoholics. Arch. Gen. Psychiatry 34, 1005-9. Hodgkinson, S.. Mullan, M. and Murray, R.M. (1991) The genetics of vulnerability to alcoholism. In: P. McGuffin amd R. Murray (Eds.1, The New Genetics of Mental Illness. Butterworth-Heinemann Ltd. Oxford. Kety, S.S., Rosenthal, D., Wender, P.H. and Schuisinger. F. (1968) The types and ;>revalence of mental illness in the biological and adoptive families of adopted schizophrenic. J. Psychi. Res. 6, 345-362. MerikaGgas, K.R. and Gdernter, C.S. 11990) Comorbidity for alcoholism and depression. Psychiatric Clinics N. Am. 13, Eii3-632. Pickens, R.W., Svikis, E.S., McGue, M., Lykken, D.T., Heston, L.L. and Clay&, P.J. (1991) Heterogeneity in the inheritance of alcohohsm. Arch. Gen. Psychiatry 48, 19-28. Pitts, F. and Winokur, G. (1966) Affective disorder: VII. Alcoholism and affective disorder. 3. Psychi. Res. 4, 37-50. Scbuckit, M. (1986) Genetic and clinical implications of aicoholism and affective disorder. Am. J. Psychiatry 143, 140147. Weissman, M-M.. Leaf, P-J ., Hoizer. C.E.. Myers, J.K. and Tischier, G.L. (1984) Tht epidemiology of depression. J. Affect. Dis. 7. 179- 188. Weissman, M.M. and Klerrnan, G.L. (1977) Sex differences and the epidemiology of depression. Arch. Gen. Psychiatry 34. 98-111. Wender, P-H., Kety, S.S., Rosenthal, D.R., Schuisinger, F.. Ortmann, J. and Lunde, I. (1986) Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders. Arch Gen Psychiatry 43, 923-929. Winokur. Ci. and Coryeli. W. (1991) Familial alcoholism in primary unipoiar major depressive disorder. Am. J. Psychiatry 148, 184-188. Winokur, G. and Pitts, F. (1965) Affective disorder: VI. A family history study of the prevalences, sex differences and possible genetic factors. J. Psychi. Res. 3, 113-123.
JAD 00924
We investigated the risk for substance abuse in the biological relatives of adoptees with affective illness, controlling for potential confounds, and additionally assessed risk by prGbands’ and relatives’ gender. Our sample consisted of 67 index adoptees with affective illness, matched control adoptees, and their biological and adoptive relatives. Both affective illness and substance abuse were more common in the biological relatives of affectively ii! adoptees than in controls’ relatives. Affective illness was more common than substance abuse among female index biological relatives, with the opposite pattern observed among male relatives.
Key words: Qepression;
Alcohol abuse; Substance
In 1986, Wender and his colleagues reported the results of an adoption study of affective disorders which they had conducted in Denmark (Wender et al., 1986). The strategy employed was that of determining the prevalence and types of psychiatric disorders in the biological and adoptive relatives of adults with affective disorders who had been adopted at an early age (the index cases), and in matched adoptees without a record of psychiatric disordars (the control cases). If
Correspondence to: Loring J. Ingraham, Room Building 10, NIMH, Bethesda, MD 20892, USA.
4Cll0,
abuse; Genetics
genetic factors contribute ao the transmission of mood disorders, one would expect to find an increased prevalence of such disorders in the biological relatives of the index cases as compared to the biological relatives of the controls. If familial psychological or other non-genetic factors play a role in the transmission of mood disorders, one would expect to find an increased prevalence of such disorders in the adoptive relatives of the index cases as compared to those of the controls. What was found - a significant increase of mood disorders and suicide among the biological relatives of the index cases as compared to the biological relatives of the controls, and no increase in mood disorders or suicide among adoptive relatives of the index cases as
compared to the adoptive relatives of controls was supportive of genetic factors in the transmission of these disorders. An additional finding was an increased frequency of alcohol and other drug abuse (subsequently referred to as substance abuse) in the biological relatives of the index cases compared to the biological relatives of the controls. In that report, the authors suggested that the observed increase in substance abuse in the biological relatives of the index cases might be an artifact of the methods employed. Diagnoses of the relatives were based on records of psychiatric hospitalization(s). The increased rate of hospitalization among the biological relatives of the index cases might have led to an increased rate of ascertainment of substance abuse in these relatives - individuals whose substance abuse was incidental and would not in itself have resulted in psychiatric hospitahzation. Another potential confound could arise if some of the affectively ill probands also had evidence of substance abuse. IIf so, an excess of substance abuse among probands’ bioIogica! relatives might reflect the operation of a genetic factor related onIy to substance abuse, and not affective illness. We have recently reviewed the literature on the relationship between substance. abuse and affective illness and have re-examined our own data to see if they could help clarify the observation of excess substance abuse in the biological reIativcs of adopters with affective illness. Over the past twenty five years a considerable and conflicting literature has developed on the genetics of affective disorders and its relations to alcoholism. Winokur’s early identification of an association between alcoholism and affective disorder (Winokur and Pitts, 1965; Pitts and Winokur, 1966) stimulated closer investigation of the rclationship between these disorders and initiated work aimed at determining whether the co-occurrence of affective disorder and Jcoholism in families represented alternate expression of the same liability. In one approach, Goodwin and his colleagues (1973, 1977a, 1977b) conducted a series of studies of adopted-away children of an altoholic parent. An increase of depression was not seen in the adopted away daughters of alcoholic fathers but was seen in the daughters of alco-
holics raised by their biologica! parents. The authors conclude that their studies neither demonstrate nor rule out the operation of a common genetic factor in akoholism and depression. Cloninger and colleagues reviewed this area in 1979 and concluded that there was a complex pattern of association among alcoholism, affective disorder, and other psychiatric disorders. in particular, these investigators noted that an increased frequency of heavy drinking, a precondition for alcoholism, may be observed in various psychiatric illnesses without necessarily implying that a putative gene for any of these disorders also plays a role in the development of alcohol abuse. Schuckit (1986) has also reviewed this area and concluded that alcoholism and affective disorder are independent diseases with some overtap in symptoms. Merikangas and GeIernter (19901 conducted another review and concluded that it was unlikely that alcoholism and depression have a common etiology. Conversely, Finn and his colleagues (1490) reported an increased risk for major affective disorder in non-alcoholic men (and their first and second degree relatives) with a muhigenerational family history of alcoholism, suggesting that alcoholism and depression may be cosegregating in these families. Active investigation in this area continues (Hodgkinson et al., 1991). Pickens and his colleagues (Pickens et al., 19911 suggest that genetic factors have only a modest effect on overall risk for alcohol abuse, but that there may be some forms of alcoholism which are moderately to highly heritable, Winokur and Coryell (1991) found an increased rate of alcoholism in the families of depressed women, (but not depressed men), and conclude that the ‘familial association between alcoholism and depression may be the result of either genetic or environmental factors or an interaction between the two’ (Winokur and Coryell, 1991, p. 184.1 Hn addition to investigating the effect of probands’ gender on the risk of illness in relatives suggested by Winokur and Coryeil’s report, it is essential to study the gender of affected relatives when investigating the relationship between affective disorder and substance abuse. Epidemiological studies indicate asymmetry in the liability
47
for affccltive disorder and substance abuse such that women arc more likely to have a diagnosis of an affective disorder and men are more likely to be identified as substance abusers (Weissman and Klerman, 1947; Weissman et al., 1984). Additional evidence suggestive of substance abuse or affective disorder as alternative expressions of a liability mediated by gender comes from the study of populations where intoxicants are not used, and therefore substance abuse does not occur. In
a study of the Amish, Egeland and I-Iostetter (1983) report similar rates of affective disorder in both men and women. In most previous studies of the relationship between affective illness and substance abuse or addiction, investigation of the independent contribution of genetic factors to the risk for substance abuse in the relatives of individuals with affective illness has been hampered by the commingling of genetic and non-genetic familial factors. Adoption designs can address this issue by separating post-natal family environ-
ment from parental genetic effects. Goodwin’s studies (1973, I977a,b) focused on a high-risk approach, following the adopted away offspring of an alcoholic parent. In this report, we have used the adoptee family strategy, which focuses on the biological relatives of affected adoptees here probands with mood disorders, and matched control adoptees free from affective disorder and their biological relatives. The strength of the adoption study strategy lies in its ability to separate the effects of genetic influences on the development of psychopathology from the effects of post-natal familial environmental influences. In psychiatric illnesses and behavioral disorders, this separation is particularly important as the similarities observed among family members may well be learned behaviors rather than the result of heritable genetic factors. MethOdS
The adoption
study methodology
has been previously described in detail elsewhere (Kety et
al., 1968). The analyses presented in this paper are based on the data previously reported by Wender and his colleagues (1986?, which have here been analyzed to address potential confounds in the diagnosis of substance abuse and to
examine the effect of probands’ and relatives’ gender on liability to illness. In brief, the index and contrul /adoptees were selected from the entire pool of 14,500 adoptees born in Denmark between I924 and I947 and who had been placed in the homes of non-relatives. The names of these adoptees were cross-indexed with a central register of psychiatrically hospitalized Gersons (the Institute for Human Genetics) and abstracts of their hospital records obtained and examined. Those who received a
consensus diagnosis of unipolar (N = 27) or bipolar (N = 10) major affective disorder, neurotic depression (N = 21; equivalent to IX&I-III dysthyrnic disorder), or affect reaction (N = 13; a Danish diagnostic category reflecting histrionic, panicky behavior or an impulsive suicide attempt) were selected from this pool as index probands; there were 48 fe.male and 23 male adoptees thus selected. For each index proband, a control proband was selected. Control probands were selected from the Danish adoption records as the closest individual in the enumerated adoption records (and thus adopted near the time of the index proband’s adoption) without a record of a psychiatric hospitalization, substance abuse, or attempted or completed suicide, and who was matched with the index proband by the criteria of gender, age, time spent with biological mother, age at transfer to adoptive home, and socioeconomic class of adopting parents. The biological and adoptive relatives of the index and control adoptees were identified through the use of the extensive Danish population registers, and records of psychiatric hospitalization. The hospital charts were abstracted and translated into English, and any identifying information that might indicate the biological/adoptive or index/control nature of the individuals removed. DSM-III diagnoses based on these records were made independently by two of the authors (Wender et al. 1986: PW, SK) and disagreements resolved by consensus. After final diagnoses were made, a research assistant de-
coded the identifying numbers and sorted the records into the appropriate biological/adoptive and index/control groups. Relatives who had died or emigrated before
reaching the age of 15 were excluded from the sample, leaving 194 male and 193 female biological index relatives and 191 male and 153 female biological control relatives.
TABLE
1
Affective disorder and substance abuse in relatives of index and control prcbands free from substance abuse * Biological
Relatives, No. (%I
As previously reported (Wender et al., 1986), a significantly greater incidence of affective disorders (Fisher exact one-tail P = 0.034) and substance abuse (Fisher exact one-tail P = 0.013) was observed in thg: biological relatives of the index cases as compared to the biological relatives of controls. There were no significant differences among the adoptive relatives. In order to test whether the greater number of diagnoses of substance abuse among index bioiogical relatives was an artifact due to the incidental observation of substance abuse in relatives hospitalized for other psychiatric diagnoses, we compared the risk for a diagnosis of substance abuse in index and control individuals who had a psychiatric hospitalization for other than substance abuse, As previously stated, psychiatric hospitalization was more common among biological index relatives than among the biological relatives qf controls, so that there was potentially a greater chance to observe evidence of substance abuse in these relatives than among control biological relatives who had fewer hospitalizations. There were 56 individuals among 386 bioiogicx ra:Iative~ and 31 individuals among 343 biological control relatives with a history of hospitaIization for a psychiatric disorder other than substance abuse (Fisher exact one-taiI P = 0.015). (There was one biological relative each in the index and control groups hospitalized with a diagnosis of substance abuse and with no other psy-
chiatric diagnosis, who have been excluded from this analysis of potential incidental observation of substance abuse.) 0f the S6 biological index relatives with a diagnosis, 20 (35.7%) also had a concomitant history of substance abuse, com-
paied with 6 09.4%) of 31 biological control relatives with substance abuse in addition to another psychiatric diagnosis (Fisher exact one-tail P = 0.087). Th e increased proportion of substance abuse observed among diagnosed biolagical index relatives makes it unlikely that the in-
Definite and uncertain Index
Control P
Substance Index
unipolar 19 (5.2) 8 (2.4) 0.03h
Adoptive ReMiVeS, No. (S-1 and bipolar disorders 3 (1.81 3 (1.9) 0.629
abuse and dependence 20 15.4)
Control
7 (2.1)
P
0.018
Total number of relrrtives 397 Index
169
328
159
Control
* There are 6 biological index relatives with both affective disorder and substance abuse who are inclued in both totals. The number of affected relatives in s-he index and control groups were compared via one-tailed Fisher’s exact probability tests.
crease in substance aDuse in the biological relatives of index probands is due to an artifact secondary to increased incidence of other dissrders. Another potential confound we wished to control was the presence of substance abuse in the affectively ill index probands; such co-morbidity might represent an independent risk of substance abuse in the probands’ biological relatives, independent of any risk represented by affective illness itself. Hf genetic contributions to substance abuse are different from those associated with affective disorders, one might obtain an increased risk for both disorders in the biological relatives of index cases with both an affective disorder and substance abuse. 0f the 71 index adoptees, 4 were also substance abusers, and these 4 index probands, along with thsir matched controls and their biological and adoptive relatives were eliminated from subsequent analyses. Table 1 presents the distribution of affective disorders and substance abuse in the relatives of
index probands free from substance abuse. The excess of both affective illness (Fisher exact onetail P = 0.046) and substance abuse (Fisher exact
one-tailP = 0.018) observed among bisbgical relatives of ill probands in the full sample He-
sents the distribution of affective
disorders and
substance abuse in the maEe and female biological and adoptive relatives of mafe and female index cases and controk, and indicaFes the percentage of affected relatives in each group. In every case for both affective tilness and substance abuse, and whether examined by gender of proband or relative, more index than control biological relatives were affected, As previously observed, adoptive relatives were at low risk for illness. Risk for affective disorder and substance
mains, supporting the finding of excess substance abwe among bislsgical relatives of affectively ill probands. As an exploratory analysis of the possible effects of gender on Biabihty for affective disorder and substance abuse, we examined the pmbands and relatives’ diagnoses by gender. In this exploratory andysis, cell sizes are smalI and geneealizability is consequently limited. Table 2 pre-
TABLE 2 Affective disorder and substance and relative *
abuse in relatives of index and control probands free from substance
Biological Relatives of: Male Probands No. I%) Definite and uncertain
Female Probands No. (%J
Relatives OF:
Male Probands No. (961
Female Probands No. C%‘c)
unipolar and bipolar disorders
Index Malerelatives Female relatives Control
Adoptive
abuse by gender of proband
Male relatives
Female relatives
2 0.3) b iP.CI
4 (3.3) 7 (5.9)
0 0
2 (3.6) 141.7)
1(1.6) 3 16.3)
2 Cl.71 2 (2.0)
0 1 (3.3)
0 2 (3.3)
5.2% of the male & female biological relatives of the male & female probands ti zre affected overall; 6.3% of M&F biological relatives of M probands 3.6% of MEF bioiogical relatives of F probands 3.3qc of M biological relatives of M&F probands 7.0% of F biological relatives of M&F probands Substance abuse and dependence Index Mak relatives Female relatives
5 (8.3) 2 (2.0)
7 CS.8) 6 IS .a!
0
l(1.8)
1 (3.4)
0
Control Male relatives Female relatives
3 (4.7) z CL11
2 (1.7) i(1.0)
0
2 (3.8) 0
5.4% of the male & female biological relatives of the male & female probands 5.5% of M&F biological relatives of M pmbands 5.4% of M&F biological relatives of F probands 6.6% of M biological relatives of M&F probands 3.3% of F biological relatives of M&F probands
i
(3.3)
were affected overall;
Number of relatives: Index Male Female
60 67
121 119
26 29
56 58
Control Male Female
64 48
118 98
25 36
53 51
* There are 2 male and 4 female biological index relatives with both affective disorder and substance both groups.
abuse whfi are inc!uded in
DeCinite and uncertain and bipolx diwrders
unip;kir
DtA’inite and uncertain unipolar and bipolar disorders & Substanw ;~buse and dependence SuMancc Chi-Square
~~tiusr and dependence \+ith 2df = h. 1-I: one-tail
4
9
Z
3
IO
3
P = (1,3X
abuse was similar b, wtn the relatives of male and female index probands. We observed a trend
for increased risk of affective illness in female biological index relatives compared with male bio!ogicaI index relatives (Fisher exact one-tail P = 0.089~. Table 3 presents the distribution of affective and substance abuse diagnoses in the male and female biological relatives of the index probands, and indicates an excess of affective disorder among female relatives and an excess of substance abuse among male relatives (Chi-Square. 2df = 5.14, P = 0.038L Controlling for potential ascertainment artifact due to differences in the number of male and female biological relatives with a diagnosis further highlights this asymmetry. Of the 23 male biological index relatives with a psychiatric hospitalization for a diagnosis other than substance abuse, 12 (52.2%) also had a history of substance abuse, compared with only 7 K?l.Y’ 1 of 32 female biological control relatives (Fisher exact one-tail P = 0.015).
The major finding of this report is an increased frequency of substance abuse in the bioIogicrll relatives of adoptties with a diagnosis of an affective disorder, even when selecting affectively ill probands free from substance abuse. Substance abuse is more frequently observed in male bioIogica1 relatives than female biological
relatives, and a converse pattern is observed in the risk for affective disorder. Some important limitations must be noted. Our assessment of substance abuse in the biological relatives of index probands was in all but one case in addition to another psychiatric diagnosis. This may limit the relevance of our findings for alcoholism or other drug addiction uncomplica ted by psychiatric comorbidity. However, the psychiatric diagnoses of the substance abusing biological relatives were distributed among a broad range of psychopathology from schizophronia to affective disorder to personality disorders, which argues against the likelihood that the substance abuse wt’ observed was a feature of a specific diagnosis (such as antisocial personality disorder) common to affected biological relatives. Our probands were selected on the basis of a psychiatric hospitalizaaiom for an affective disorder, and so our findings may be limited to more severe affective illness. However, by restricting our study to the relatives of individuals with a hospitalization for affective illness, we may have been able to study a more homogeneous group of probands than in studies of milder or mixed psychiatric disorders or in studies of alcoholic probands. If there is a common genetic liability for some affective illness and substance abust: which is mediated by gender, then we would expect to see these illnesses segregating by gender within the biological families of adoptees. In most of the families we studied no more than one biological relative was ill, and in only three of our families was there at least one diagnosis of affective illness or substance abuse in both a male and female relative. In this very small subsample of three families, affective illness was seen exclusively in female relatives and substance abuse was seen in both male and female relatives. Offsetting the potential limitations of our design and sample are some notable strengths. In particular, the adoption study design used here separates the effect of family environment from that of genetic liability. The use of control adoptees and their biological relatives permits the conclusion that the distribution of substance abuse observed reflects more than a general tendency for males to be more likely to be identified
51
as substance abusers, and that the observed increase is specific to the biological relatives of affectively ill probands. In conclusion, the present analysis provides evidence for a genetically transmitted liability for substance abuse as well as affective disorder among the biological relatives of ind: Aduals with a history of affective disorder. Furthermore, liability in relatives for affective disorder or substance abuse is related to gender such that female relatives of affectively ill individuals are at greater risk for affective illness than substance abuse, while male relatives have a greater risk for substance abuse.
We acknowledge with appreciation the collection and abstracting of Danish records by Drs. J. Ortmann and 1. Lunde.
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