Sn Genetic and Environmental Effects on Offspring Alcoholism New Insights Using an Offspring-of-Twins Design Theodore Jacob, PhD; Brian Waterman, MPH; Andrew Heath, PhD; William True, PhD, MPH, Kathleen K. Bucholz, PhD; Randy Haber, PhD; Jeff Scherrer, MA; Qiang Fu, MD, PhD Context: Although there is now considerable evidence that _genetic effects play'a critical role in the development of al- cohol dependence (AD), theoretical and methodological limitations of this literature require caution in describing the etiology and development ofthis disorder. Objectives To disentangle genetic and environmental effects on AD by means of the infrequently used, yet po- tentially powerful, offspring-of-twins design. Designs Olspring of wins. Participants: Male monozygotic and dizygotic twins con- ccordant oF discordant for AD and control pairs from the Vietnam Era Twin Registry were assessed, as were the off spring of these twins and the mothers ofthese offspring, jerventions: Structured psychiatric interviews, Main Outcome Measures: Participants’ psychiatric, alcohol abuse (AA), and AD histories (DSM-IV) Results: Oifspring of monozygotic and dizygotic wins witha history of AD were significantly more likely 106 hibit AA or AD than were ollspring of nonalcoholic fa- thers. Olfspring of an alcohol-sbusing monozygotic twin whose co-twin was AD were also more likely to exhibit AD than were oflspring of nonalcoholic twins, In con- trast, offspring of an unaffected (ie, no history of abuse or dependence) monozygotic twin whose co-twin was AD were no more likely to exhibit AA or AD than were off- spring of nonalcoholic twins. Conclusions: These findings support the hypothesis that family environmental effects do make a difference in ac- counting for ollspring outcomes, in particular, that a low- risk environment (ie, the absence of parental alcohol- ism) can moderate the impact of high genetic risk regarding ollspring for the development of aleohol-use disorders. Arch Gen Psychiatry. 2003;60:1265-1272 HE AIM of the present project is to examine the impact of genetic and en- vironmental factors on al coholism through use of ping research traditions with distinct strengths and limitations."="" The psychosocial research tradition has (1) developed increasingly sophist cated models of etiology, (2) defined a va- From the Palo Alto Veterans Afjrs Health Care Systm, ‘Menlo Park, Calif (Drs Jacob aan Haber) the Saint Lous Veterans Afairs Medical Center, St Lous, Mo (tr Waterman) the Department of Psychiatry, Washington Unversity School of Medicine, St Louis (rs Heath and Buchol); and the Schoo of Public Health St Louis Unversity Drs True and Fuand Mr Scher). (aepnanreD) TECH the infrequently used, but potentially pow- erful, oflspring-of-wvins design. In so do- ing, our intent is to better appreciate the relative effect of the alcoholic family en- vironment in elevating alcobolism risk be- yond that associated with genetic risk for the disorder, FAMILY STUDIES OF ALCOHOLISM That children of alcoholics (COAs) may beat increased risk for alcoholism, other psychiatric disorders, and general psycho- logical and interpersonal impairments has been discussed in the elinical and scien- Lific literature for many decades." Much of the extant work in this area has been conducted by 2 relatively nonoverlap- (©2003 American Med jamanetwork.comy/ on O1/16/2021 riety of key mediator and moderator mechanisms that may account for oF qualify the impact of family history risk on offspring outcome, and (3) produced several high-quality, longitudinal datasets aimed at testing alternative models of me- diation and moderation.""" The major shortcoming ofthis line of research is one of ambiguity of findings, since all such ef- forts have involved simple family studies so that separation of family genes from family environments has not been pos- sible. In contrast, behavioral genetic stud- les have offered an increasingly persua- sive argument that genetic effects ultimately account for 40% to 60% of the variance in alcohol dependence (AD) risk and that the remaining variance is only 1 Association, All rights reserved.partly explainable in terms of shared family environmen- tal effects." The strength of these conclusions, how- ‘ever, must be tempered by several substantial limita- tions.® Most important, litle is known about how genetic effectsare mediated and moderated by environmental ef- fects, that is, the nature of gene-environment correla- tions and gene-environment interactions relevant to the ‘eiology and course of alcoholism. Failure to assess per Uinent shared environmental risk factors may be espe- cially problematic for studies of genotype X shared en- vironment interaction effects, since in the classical win design these interaction effects, unless explicitly mod- led, will be confounded with the genetic main effect." THE NEED FOR ALTERNATIVE GENETIC DESIGNS ‘Of the various research designs that have been used in family studies of AD, each is characterized by strengths and limitations’: (1) the family study method does not permit resolution of genetic and environmental causes of parent-ollspring resemblance; (2) the classical twin de- sign confounds estimates of genetic effects and {genotype shared environment interaction effects; (3) the adoption design studies a limited number of indi- Viduals raised in high-risk environments, since adop- live parents are typically older, of higher socioeconomic class, unusually motivated to provide a nurturing envi ronment for their adoptive child, and, at least by self selection (if not by agency screening), unlikely to ex- hibit a wide range of characteristics that could have an Important impact on the child's development’ and (4) the wins-reated-apart design is another potentially pow- erful method, although most of these results are mainly informative about consumption rather than AD." The offspring-of-twins design” has been used less often in behavioral genetic studies of psychiatric disor- ders, and, to our knowledge, never in a rigorous assess- ment of AD etiology. This approach provides a power- ful pseudoadoption design''* in which genetic and ‘environmental risk status can be inferred from the co- towin's history of alcoholism. Most important, children raised by an alcoholic monozygotic (MZ) or dizygotic (DZ) twin parent are at high risk for psychiatric disor- ders and other health problems because of high genetic risk and high environmental risk. In contrast, children raised by the nonalcoholic twin of an alcoholic MZ co- twin are at low environmental risk because these chil- dren have not grown up in an alcoholic home, but they areat the same (high) genetic risk as the children raised by an alcoholic twin because the fathers have identical ‘genotypes. In turn, children raised by the nonalcoholic twin ofan alcoholic BZ co-twin are also at reduced (low) ‘environmental risk but at only intermediate genetic risk because DZ twin pairs on average share only half of their zgenes.° Given these differences in risk profile, the child of an alcoholic parent should be no more likely to develop. alcoholism than the child of « nonalcoholic parent who is an MZ co-twin of an alcoholic individual in the ab- sence of any environmental effect of parental AD. On the other hand, excess rates of alcoholism inthe former group, (aepeanteD) TET (©2003 American Med jamanetwork.comy/ on O1/16/2021 after controlling for psychiatric disorders and assorta- Live mating, would imply an environmental impact of pa- rental alcoholism. The addition of DZ win pairs and their spouses and offspring is eritical for clarifying interpre- tations of findings; that is, without this group, equally elevated rates of alcoholism in the offspring of alcohol- icsand of nonalcoholic MZ co-twins of alcoholics could be explained by either genetic transmission or environ- ‘mental effects of a risk factor for which the twin pairs were perfectly correlated (eg, religious affiliation). Fur- ther discussion of these various genetic designs can be found in several sources"? The present study assessed male MZ and DZ twins concordant oF discordant for AD oF concordant for no AD nd their biological offspring and the biological moth- ers of their oflspring. Three major hypotheses guided our analyses: 1. The prevalence of offspring alcohol abuse (AA) and AD will be highest for the biological children of an aleohelic parent (ie, alcoholic fathers from either MZ oF DZ pairs) and lowest when fathers exhibit AD and have no elevated genetic risk forthe disorder (ie, father's co- ‘win is nonalcoholic). This hypothesis s based on asize- able literature indicating that COAs exhibit higher rates of alcohol-se disorders than do non-COAs 2. Inthe absence of paternal AD. offspring with el- evated genetic risk (ie, where the unafeeted father’s MZ DZ co-win isaleoholc) will exhibit lower rates of AD than will COAs, Dilferences in rates of ollspring alco- holisin willbe greater between COAs and children oftheir uunallected DZ. twins than between COAs and children of thei unaffected MZ twins given the lower genetic load- ing in the former vs the late. This expectation is based on the contention thatthe environment associated with parental alcoholism—not just parental genes—allects olf Spring development (albeit perhaps in interaction with rmuluple offspring genetic vulnerability) through im- pact on family stability, parenting practices, and sibling relationships: modeling effects; and general socioeco- homie satus." Finally differences between COAS and offspring of control MZ and DZ twins (from con- cordant unaffected twins) would be explained in terms of differences in genetic and environmental risk 3. To the extent that AA and AD represent difer- ent points along the same continuum of risk, as sug- gested by several studies" using latent class analysis, the impact of no parental alcohol problems, parental AA and parental AD will result in diferent risk profiles for offspring. tn particular, a child with high genetie isk (be- cause the fathers MZ co-twin is AD) is not necessarily at low environmental risk his or hee father exhibits AA but not AD, Se PARTICIPANTS Data for clasifying twins were derived from interviews per- formed in 1992 with members of the Vietnam Era Twin Reg- istry.® The Registry i composed of male-male wvin pairs horn between January 1, 1939, and December 31, 1957, who served inthe US military between May 1, 1965, and August 31,1975." 1 Association, All rights reserved.tn 1987, wins completed a mailed questionnaire of general Health rom which data on thelr biological offspring, fnlud- ingsex and age, were obtained In 1992, Registry embers were fninistered telephone peychati diagnostic interview cov- ring arange of disorders, including alcohol and drug depen- Alenees" Twin pairs were selected based on the following cr teria (1) completed the 1987 and 1992 surveys, (2) reported having children born between 1974 and 1988, and (3) Went fed ax concordant or dscordan for alfetime dagnossof DSM UL AD or asa member ofa random sample of non-AD con- trol pats, We targeted asumnpl of 144 wits (732 pats), their clulren, andthe childrens mothers, Terms of the human subject approval from the intu- tional eview boards of the particpaing nsutlons required that thewin be conaced fs to obtain permission to contact moth ttsand children, Then, the mothers were contacted for partic pation and for permission to contact the children, otha, li tnaely, child participation required contact of and permission from both patents OF the eligible twins, 1213 (89%) par pated inthe clephoneimeview. Participating twins Wentfed End pie consent to comact 1070 mothers, of whotn 892 (81°) Parlcpated inthe tlephone interview. Consent rom both par ffs to comlact ther children was obtained for 1487 offeping Of these, 1270 (85%) participated inthe telephone interview ‘The nonpartcpating twins, mothers and ofspring were de- censd, unable fo be located, or unavalable, of they tefused to take pat in the stndy. To assess for potential sample bis and impact on generalizability of findings we developed and tested 4 todel of offpring response asa function of parental and of- spring characteristics, Results indicated that (1) the alcoholism Sous of the lather was not a igiican predictor of offepring Participation, (2) only ollspring sex was seaciated with refusal {opartat ales ect than females), sampling weights Aletived trom paternal sociodemographic variables could cea ture the distribution of key variables inthe target population, and @) nonresponse bias was minima. ASSESSMENT. CComputer-asssted telephone interviews were conducted by trained interviewers from the Institute for Survey Research, ‘Temple University, Philadelphia, Pa. Offspring were adminis tered a modified telephone version of the Semi-Structured As sessment for the Genetics of Alcoholism interview” that per- mited determination of DSM-IV *lileime ad current diagnoses ‘of AA, AD, major depression, childhood conduct disorder, op- positional defiant disorder, anxiety disorders (including so- al phobia, panic with and without agoraphobia, and gener- alized anxiety disorders), nicotine dependence, cannabis dependence, and abuse of 7 classes of drugs. In addition, non- diagnostic sections—including suicidality; raumaticevents; ex tensive drug-, tobacco-, and alcohol-use histories; and sextal rmaturation-—were covered. The present study focuses on olf spring AA and AD as the outcomes of interest. The maternal interview, also administered in computer-ssisted telephone in- terview format, covered her own DSM-IV history of AA, AD, and major depression and included sereens for drug use, nico- line dependence, mania, antisocial personality, and her use of| substaices foreach of her pregnancies with the children, Moth- cers were also asked about their children's behavior, including attention-deficivhyperaetivity disorder, conduct, major de- pression, alcohol use, and various nondiagnostic sections on rearing history and family background. For the win fathers, ‘extensive psychiatric histories had been obtained in 1992 dur ing their participation in the Harvard Drug Study, so that the assessment forthe present study included a shor interview cov- ‘ering primarily their alcohol-use and problems history, using aan adaptation ofthe Lifetime Drinking History.” (aepeanteD) TET (©2003 American Med Downloaded From: https:/jamanetwork.com/ on 1/16/2021 DATA ANALYSIS For primary analyses, we used a 6-group classification scheme based on the AA and AD histories of the twin parent and the parents co-twin: group I consisted ofa twin father (whether MZor DZ) with ahistory of AD and an MZ or DZ co-twin with any or no diagnosis; group 2, twin father with A and an AD, MZ co-twin; group 3, an unaffected twin father (no history of AAor AD) and an AD MZ co-twin; group 4,2 twin father with ‘AA and an AD DZ co-twin: group 3, an unaffected twin father and an AD DZ co-twin; and group 6, both twins, whether from MZor DZ pairs, unaffected. Covariates included maternal AD, AAA, and depression: paternal depression, antisocial personal- lay disorder or conduct disorder, and illicit drug abuse or de- pendence; marital status (ever divorced); paternal educational and employment status; and offspring age and sex. In initial descriptive analyses, we tested for sociodemographic differ ences asa function ofthe 6 risk groups, using linear or logistic fegression models ta predict exch sociodemographic outcome ‘essure asa function of 5 dummy variables corresponding to the risk groups and using group 6 controls asthe comparison _group. We then estimated a polylomous logistic regression model to jointly model the risk of (1) AD and (2) AA, relative to no alcohol diagnosis, as a function of the same 5 dummy vari ables and relevant contol variables. Odds ratios and their 95% confidence intervals are reported for these analyses, estimated using the Huber-White robust variance option to correct for observations on multiple individuals from thesame family (fll orhalf siblings from the same father or cousins related through the father and the father’s co-twin)." ‘A critical assumption underlying our use of clasifica- tion with 6 risk groups is thatthe same familial factors (ge- netic or shared environmental) that determine risk of AD also determine risk of AA in those who are not dependent on alcohol. To test this hypothesis, a standard bivariate genetic model was fitted to data from the entire Harvard Twin study sample on (1) number of DSM-IILR AD symptoms and (2) history of DSN-E-R AA (defined as a binary variable but set to missing ifa twin met the criteria for AD). Model fiuing was conducted by the method of maximum likelihood using a quadrivariate normal multiple threshold model using the MX statistical program’ (see Heath and Nelson" for technical details of this approach). Results indicated that neither the genetic correlation nor the shared environmental correlation between AA and AD differed significantly from unity (P>.05). These results validated our 6-group classifi cation scheme. (es SAMPLE CHARACTERISTICS There were approximately 1.8 siblings per family; twin fathers and mothers averaged 50 and 47 years of age, r spectively; more than 50% of fathers had greater than a high school education, and 90% were employed full ime atthe time of the study; and offspring (approximately 52% male) ranged in age from 12 to 26 years (SD=4.0 years) (Fable 1). Although there were no significant crose-group differences in these family characteristics, pa- ternal education (as expected) differentiated AD from nnon-AD fathers (t,,9;,P<001) and AD twins from their nonaffected co-twins Within AD discordant pairs (t,o, P<.) 1 Association, All rights reserved.‘Table 1. Sociodemographic Characteristics of All Participants by Paternal Alcoholism Status ‘to, z, ond —_withabuse;—_Unatectee; with abuse: ——_unafcig;,——_Unattectog DzTwine coin WithAD —co-twin itAD co-wln Wn/AD.co-win Wit AD. coal Tne charctrtte (a=387) (w=94) (ner) (vse) (m=z Sing, mean (SD), No 173003) 163.0205 (123) «1.8888 «tN «TTL Child age, man ($0) y iaeiat) 19488) 105(41) 187 (40) 1488) 19640) Patera age, mean ($0), 502460) 5057220) 097/278) © 9043243) 5028(251) 005 254) Materal age, mean (5D), y 737 @a) 9776(@60) 73D UBM) 498) ATATRBH) 4831 8D) Male spa, % 489 an 582 507 505 45 Father employed ul tine, % 950 soa ons sro mas 7 Father graduated tom highschool 57.4 saa 640 eri2 a2 2 Mosher rausa rom igh shoo, "6 692 nr 508 Tad a2 na Parental matt sts divorced,‘ 220 21 85 ma 1s 165 White ae,“ ea or 100 985 ooo uz Neral AD, %| na 162 75 105 44 65 neal lahol abu, a 76 15 ar 67 52 Materal depression, % 172 a1 0 149 ua ng Paternal psyehiaicdsorder, ot a5 132 138 164 184 31 ‘Abbrviaons: AD sleool dependence: OZ dagot MZ, monoaygte “igh zevn can of contol tons ha prevous Gagnon sleool abuse ony. Tate cases ware ramoved rom th sample oad retry to comgarsoas invlingurtetad han "Based on previous DSM dagnass of conuct sore anscial personality soda and maj depressive csodr,18y Male sping Male tsping age >18y Grater than high schol education Engloyed Diced 700 700 1168 1.07249)" 222,140.86)" 205 (08847) 307 (1207271 074 036150) 080 034-190), ‘ez 076308) 1.05 (030-282) 60 (030-158), os7(o3t227) 1.42 058-300) 072025200) 116 050223), 125(082-257) 1.09(030300) 254 087-955), st (042-133) 060 034140) sr (05¢140), 094 056-158), 308 1.60563)" 3.6 (155775)° 079 036171) 047 015-148) 214 t166e ‘az(n0158)" 1.98 07-449) 1158 1.00234)" 5.5 154-1863)" 1.18(097-148) 074030139) 176(110-28)" Abbreviations: DZ ingot; MZ, monozygotic pes feat ‘Bla depression, antisocial ersnaty disorder, or conduct disordet Compared with groups 1 and 2, offspring at high ge- netic but low environmental risk (group 3) were signifi- cantly less likely to exhibit AA ('=6.02; P=.01) or AD, (25.1; P=.24), and this latter group did not differ in risk from those at moderate genetic but only low envi- ronmental risk (group 5) (AA: x'=0.02; P=.90; AD. (03; P=.87). Finally, risk differences between groups Tand 2 and group 4 (moderate genetic risk and moder- ate environmental risk) approached significance for AD (¥'=3.0; P=.08) but not for AA (x'=0.00; P=.97) ASSESSING FOR GROUP DIFFERENCES IN GENETIC LIABILITY To ensure that differences between groups Land 2 and ‘group 3 resulted from the protective effects of a nonal- ‘coholic family environment and not from differences in ‘genetic linbility, we examined oflspring outcomes among 6 subgroups within group 1. Here, all twins, MZ or DZ, were AD, whereas co-twins could be (1) AD MZ, (2) AA MZ, (3) unaffected MZ, (4) AD DZ, (5) AA DZ, or (6) uunalfected DZ, Using a multinomial logit model, results indicated that offspring of AD fathers whose MZ or DZ ins had a history of AA or AD were no more likely to exhibit AA of AD compared with olfspring of AD [a- thers whose MZ oF DZ co-twins were not affected. Odds ratios ranged from 1.00 to 1.83, and all are associated with (95% confidence intervals that included unity. Purther- mote, results confirmed the homogeneity of odds ratios for group 1 across co-twin zygosity. Odds ratios ranged from 0.43 to 1.46, and all were associated with 95% con- fidence intervals that included unity. These results sug- ‘gest that an offspring with an alcoholic father whose co- twin is not affected isat no less genetic risk than the child ‘ofan AD father whose co-twin is AA of AD. (apna TED) ARCH GEN PNCHINTROL GD, DEC TO (©2003 American Med jamanetwork.comy/ on O1/16/2021 eee Although the familial transmission of alcoholism risk is beyond doubr, there has been continuing controversy as to the nature of these familial effects for many decades. Many psychosocial researchers and most clinicians, for example, argue that parental alcoholism alters the fam- -nvironment and that these family changes—be they disturbances in parenting, the parent-child relation- ship, modeling effects, economic stability, or more gen- eral family-level disturbances—are the operative effects {or explaining the eventual development of alcoholism. For these observers, the conclusion that genetic and en- vironmental effects matter but that the latter are not sys- tematically related to what happens within the family to rake siblings alike would be vigorously disputed. Given the serious and recent criticisms of the behavioral ge- netic perspective, "= together with concerns that ge- neticists themselves have discussed regarding limita- ons to their approach, continued examination of the etiology of alcoholism remains essential The offspring-of-1wins design offered a relatively strong test of the hypothesis that family environmental fects make a difference in accounting for ollspring out- comes. Four of our findings are particularly noteworthy First, offspring of alcoholic fathers (group 1) were at significantly higher risk for alcohol-use disorders than were offspring of controls (group 6: low genetic and low environmental risk), results that concur with the often reported finding that alcoholism “rans in families."* Al- though such a finding is “necessary” for building a fam- ly theory of alcoholism, i tells us litle about the nature of the family effects, hence the need for more informa- Live group contrasts that help specify the nature of such family relatedness. 1 Association, All rights reserved.Second, the contrast between groups 1 and 3 speaks most clearly to the impact of nongenetic family effects ‘on offspring alcoholism. That is, inthe absence of an al- ‘coholic family environment—even with high genetic risk for the disorder—offspring alcoholism outcomes were similar to those of controls (low genetic and low envi- ronmental risk). Furthermore, there seemed to be no dif ference in impact on offspring of paternal AD (group 1) and paternal AA (group 2) as long as the father had an [AD MZ co-twin, Ollspring in both of these groups were similarly at heightened risk foralcohol-use disorders, and both were at greater risk than offspring [rom group 3. Stated otherwise, given a background of heightened ge- netic risk, moderate levels of paternal alcohol-related prob- lems (paternal abuse) provided no protection compared ‘with severe levels of paternal alcohol-related problems (paternal dependence). What this means—if the pres- cent findings prove to be replicable and generaliz- aable—is that genetic risk in many cases becomes acti lized only if there is some significant environmental ‘sequela to the genetic vulnerability. That is, genetic risk may be necessary but not sufficient for offspring alco- holism to develop. Although we cannot yet specify what particular family environmental factors are present when the father expresses AA or AD and absent when he does not, the larger alcoholism literature has suggested vari- ‘ous possibilities: the impact of paternal AD on marital and parent-child relationships; drinking models and drinking-relevant cognitions and experiences; in- creased risks of raumatic experiences stich as rape, mo- lestation, and physical abuse"; and the family’s eco- nomic well-being.?? What we do know, however, is that the outcome dif- ferences between groups 1 and 3 eannot be accounted for by group differences in maternal AD, depression, or antisociality or in paternal depression, antisociality, oF ‘educational and occupational status; that is, these varl- ables were covariates in our primary analyses. Neither ‘ean these differences be explained by differences in ge- netic liability for groups 1 and 3 given out findings that ollspring of AD fathers whose MZ oF DZ co-twin had a history of either AD or AA were no more likely to ex- hibit AA or AD than were offspring of AD fathers with ‘an unaffected MZ or DZ co-twin, Further clarification of specifi family environmental effects that differentiate the ‘environments of families with and without an AD father ‘would be of great importance. is straightforward to reconcile these findings with, results from twin studies of AD and AA. In the tadi- tional twin design, comparing MZ and DZ win pairs reared together, genetic effects and gene X shared envi- ronment interaction elfects are confounded." The rela- lively weak evidence for shared environment effects on [AD risk from such twin studies” would be consistent ‘with the notion that the environmental effects associ ated with parental AD or AA are dependent on offspring ‘genotype, that is, that genotype X shared environmental Interaction effects are important." On the other hand, adoption studies have not, in general, suggested an im- portant role for alcohols in adoptive parents in the trans- mission of alcoholism risk.” In attempting to reconcile ‘our results with this literature, several possible explana- (aepeanteD) TET (©2003 American Med jamanetwork.comy/ on O1/16/2021 Lions can be offered. Typically, as in the ease of the lowa adoption studies"! and the Swedish adoption stud- 2 alcoholism cases were identified from official re rds and thus may have disproportionately represented the most severe alcoholic individuals and those with an- tisocial traits, for example, the elevated rates of temper- ance board registrations of biological fathers compared ‘with genetal popiilation rates in the Stockholm Adop- tion Study." Given these considerations, it seems plau- sible the these offspring are at very high levels of genetic risk, In general population samples, however, such as those represented in the Virginia, Australian, and Viet- nam Era twin samples, only a few AD cases will be verely affected. The high prevalence of DSM-IIE-R AD in the Vietnam Era Twin Registry sample, which reflects the rather broad definition of the disorder in this registry, is consistent with the contention that we are dealing with, con average, less severe cases of paternal AD and thus lower levels of genetic risk in the offspring.” In light of these considerations, we suggest that for individuals with the highest levels of genetic risk, shared environmental and genotype X shared environment elfects on risk may be relatively unimportant but that for individuals with less extreme levels of genetic risk (who may well represent most individuals who become AD in the general popu- lation), genetic and genotype shared environment i teraction effects may assume greater importance in dé ermining offspring outcomes, A third finding was related to our expectation that children of unaffected fathers would fare better than chil- dren of AA fathers and that both would fare better than children of AD fathers. But as seen, the offspring of AA fathers looked very much like their counterparts with AD fathers, meaning that there was no “partial” protection associated with the milder forms of the disorder within the MZ group. The absence of such a continuum of ellect may be understood in several ways: (1) high-risk em ronmental expostre associated with paternal AA is sul- ficiently disruptive to potentiate the genetic risk into e pressed disorder, (2) there may have been various episodes ff abuse during the father’s parenting years that trans- lated into a more chronic course and therefore a signil cant impact on the family environment (both of these e planations seem to be consistent with our finding in the Vietnam Era Twin Regisity owvins that AA and AD share genetic and family environmental risk factors in com- mon);and (3) some of the AA diagnoses may have arisen because of underreporting of symptoms when in fact AD would have been the more appropriate diagnosis, A final result was the absence of differences be- tween groups 3 and 5 (ie, between offspring of unal- fected twins with AD MZ co-twins vs AD DZco-twins) and the absence of differences between the controls (group 6) and all moderate-risk groups (ie, ollspring from groups, 3, 4, and 5). As recalled, our hypotheses were based on theoretical considerations regarding different levels of ge- netic and environmental risk associated with group sta- tus, For example, group 3 is at higher genetic risk than groups 4,5, or 6, whereas groups 4and 5 are at the same genetic risk, but group 4 is a higher environmental risk than group 5, whereas group 5 is at higher genetic risk (but similar environmental risk) than group 6, and so on. 1 Association, All rights reserved.1m considering the findings that differences in the prevalence of offspring AA and AD were not ordered in terms ofthese expectations (ie, group 3>group 4>group 5>group 6), it should be remembered that the preva~ lence of aleohol-use disorders isat its highest during the adolescent to young adult years so that it may be more difficult to differentiate offspring risk at this age in terms of our varying genetic and environmental profile. Our sample contained many minors who have not yet passed through the major risk period for the development of al- cohol-use disorders.” With the passage of time, how- ever, those at lower risk would be expected to adopt pate terns of nonproblem drinking, whereas those at higher risk would be expected to exhibit continuous or inter- mittent problems of AA or AD. If rue, future fol- low-up assessments ofthis sample should provide addi- tional information on this issue, which, in turn, would motivate us to revisit our study hypotheses. ‘Submitted for publication September 25, 2002: final revi- sion received May 9, 2003; accepted May 13, 2003. This study was supported by grants AAI1667 and AA11822 and center grant AA11998 from the National In- ‘stitute on Alcohol Abuse and Alcoholism and by a Merit Re- view Grant from the Department of Veterans Affairs Medi- cal Research Service, Washington, DC (Dr Jacob). Corresponding author and reprints: Theodore Jacob, PhD, Palo Alto Veterans Affairs Health Care System, 793 Willow Rd, MC 151-J, Menlo Park, CA 94025 (e-mail: acobi@pesp.edu), EES} Neue M.A biti gestc ppt on chin of eho. Aad ea ae Worl, 18721230. Shar Psjhuloial crac tele of ahs, Aaa Heath Fes Wort 00721247254, 4. Sherk Chiltan af coos ite Avast Tey and Reseach Chi 0 I Unversy f Cao Pres: 10 Whe Conca ant iss in GOK research Aaa Hat es Word 157, pia5-0h ‘Wine Sos Chison of Aosta. New Yak MY Gs Pbietone190. 6 die Ty, Sher, Buco KK, Tue WT, Sag El Roba Nan Huan, To, Sats WS Wit Ke K Marin, Man PA Haat AC. An iterate arose or shin th logy of soho a thr etn. Tin Ber 200410818, 1, deeb, Leona Family ad per intsnesin he deeopnent of af ‘etalcha abuse. Zula Roy 6, Howard Jes, Deveopmet of Aco at Protons: Exptoing te Bopsyhoscl Maro sk Washo, DC: Nina nett on Aeon! Rose ad Ahoy, 84, 8 lis 04, Zukr RA, Fer HE. Tha oo amily inenesin developer and sk Aol ath es Wot 19721-28-28. ©. 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