Alcohol Abuse and Family

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THE HERITABILITY OF ALCOHOL ABUSE

AND DEPENDENCE: A META-ANALYSIS

OF BEHAVIOR GENETIC RESEARCH

Glenn D. Walters*

Psychology Services, Federal Correctional

Institution-Schuylkill, P.O. Box 700, Minersville,

PA 17954-0700

ABSTRACT

A meta-analysis was performed on 50 family, twin, and adoption

studies in which problem drinking and alcohol dependence served

as the primary criterion measure. The results showed that far from

being an established “fact,” the genetic foundations of alcohol

misuse are modest and heterogeneous. A weighted mean f effect

size of 0.12 (95% Confidence Interval ¼ 0.11– 0.12) was obtained

for the total sample of 72 effect sizes. Four potential moderator

variables (proband gender, sample nationality, pattern severity,

year of publication) were examined with outcomes confirming

that the heritability of alcohol misuse is stronger in males and in

studies employing more severe definitions of abuse (alcoholism,

alcohol dependence). When the effect size measure was restricted

to studies using male subjects with more severe diagnoses of

alcohol misuse, the unweighted mean f effect size was only 0.18

(95% Confidence Interval ¼ 0.15– 0.21), with an even smaller

557

Copyright q 2002 by Marcel Dekker, Inc. www.dekker.com

*E-mail: [email protected]

AM. J. DRUG ALCOHOL ABUSE, 28(3), 557–584 (2002)



weighted mean f effect size of 0.15 (95% Confidence Interval ¼

0.12–0.18); results which indicate an upper limit of 30–36% for

the heritability of alcohol misuse.

Key Words: Alcohol; Alcoholism; Genetics; Heredity; Meta-

analysis

In June 1990 the Journal of the American Medical Association (JAMA)

published a paper by a group of researchers from the University of Texas

Health Science Center in San Antonio claiming that a genetic locus for alco-

holism on the Taq1 A1 allele of the dopamine D2 receptor (DRD2) gene had

been identified.[1]

The news made headlines in several newspapers, was writtenup in at least one national magazine, and was broadcast to millions over the

evening news. The normally reserved New York Times called it a major break-

through in the fight against alcoholism.[2] However, when JAMA published

another paper 8 months later refuting Blum et al.’s original findings[3] the news

met with none of the fanfare that had greeted the original Blum investigation. If

the Bolos study was mentioned at all it, was relegated to the back pages of

a handful of newspapers and trade magazines. Hence, much of the general

public still believes that a gene for alcoholism exists, [4] even though the bulk of

recently published studies on the DRD2 gene shed serious doubt on its status as

a marker for alcohol misuse.[5–9]

It is understandable that people would want to believe news that a gene

responsible for a pattern that causes serious physical, social, and economic

problems in three out of ten American families[10] had been discovered. After all,knowledge promotes control which, in turn, reduces fear and instills hope.

However, if the knowledge is false or inaccurate then disappointment, frustra-

tion, and mistrust will surely ensue. The human genome is comprised of nearly

100,000 genes, 20,000–30,000 of which involve brain function.[11] That any one

of these genes accounts for more than a modicum of variance in a behavioral

pattern as intricate and multifaceted as alcohol misuse seems highly unlikely. The

DRD2 gene may well contribute to alcohol misuse but only as part of a much

larger polygenetic pattern. Schork and Schork [12] note that multiple genes can

influence complex patterns like alcohol abuse and dependence in one of five

ways: (1) general additive effect (the presence of several genes from a larger gene

pool); (2) threshold effect (the proper number of genes); (3) epistasis or gene

interaction (the proper combination of genes); (4) locus heterogeneity (more than

one gene can activate the pattern); and (5) any combination of the four previously

mentioned possibilities. The complexity of both genetics and alcohol abuse

makes it that much more difficult to believe that any one gene is responsible for a

major portion of the variance in alcohol misuse.

WALTERS558



Before accepting the view that alcohol misuse is genetically transmitted

and that heritability for alcohol abuse is upwards of 40–60%,[13] we must first

consider the growing body of behavior genetic research on this issue. Behavior

geneticists seek to identify the relative inheritance of complex patterns like

alcohol misuse with the aid of three primary methodologies: family studies, twin

studies, and adoption studies. The rationale behind family studies is that if a trait

or pattern is genetic then it should be more routinely observed in people with a

family history of problem drinking. In other words, the trait or pattern should run

in families. Outcomes obtained in early family studies on alcohol abuse and

dependence revealed that people with a family history of alcohol misuse were

three to four times more likely to personally misuse alcohol than persons without

a family history of alcohol misuse.[14] In so much as most families share expe-

riences as well as genes, the family method confounds biology (genetic inheri-tance) and environment (learning). This has led to the development of twin

and adoption methodologies in behavior genetic research.

The twin method is grounded in the fact that identical or monozygotic

(MZ) twins are genetically identical, whereas fraternal or dizygotic (DZ) twins

share half their genes in common. A genetic influence is therefore implied, at least

in theory, when MZ twins display greater similarity or concordance for a trait,

behavior, or pattern than DZ twins. However, twin research rests on a tenuous

foundation of controversial assumptions. The first assumption made by supporters

of the twin method is that parental mating is random or nonassortative. Studies

addressing this issue in alcohol abusing populations have met with conflicting

results, with some studies identifying moderate levels of assortative mating in the

parents of alcohol abusers[15] and other studies showing no evidence of assortative

mating in the mothers and fathers of alcohol abusers.[16] The equal environmentsassumption, a second supposition advanced by proponents of the twin method,

maintains that MZ twins are raised in environments that are no more similar than

the environments in which DZ twins are raised. Despite assertions by twin

researchers that the equal environments assumption holds up under empirical

scrutiny,[17] there is evidence that MZ twins develop significantly closer

relationships[18] and have more contact with one another than DZ twins and that

such closeness is associated with increased similarity in drinking patterns.[19]

The adoption method compares individuals adopted in early childhood

with their biological and adoptive parents on patterns like alcohol misuse.

Although the adoption method is considered superior to the family and twin

methods, it, like the other two methods, is not without limitations. Problems with

the adoption method include failure to account for time spent with the biological

mother prior to adoption, prenatal influences, and selective placement;[20] more

specific concerns have been raised about the three major adoption cohorts in

which alcohol abuse patterns have been studied. The Goodwin et al.[21,22] Danish

adoption studies, for instance, have been criticized for employing confusing and

HERITABILITY OF ALCOHOL ABUSE 559



arbitrary classification criteria and a sample comprised largely of young adults

who had not yet passed through the age of greatest risk for alcohol misuse.[23] The

Swedish adoption studies,[24,25] on the other hand, have been reproached for

relying on temperance board data because these data may confound alcohol and

criminality.[26] Finally, research on Iowan adoptees[27,28] has been criticized for

basing diagnoses of biological parent alcohol misuse on second-hand and

potentially unreliable information.[29]

There are several variables that potentially moderate the relationship bet-

ween heredity and alcohol misuse. One such variable is gender. It has long been

speculated that addictive liability for alcohol is higher in males than females. As

Hill and Smith[30] point out, however, this does not rule out a genetic effect for

female alcohol abuse and dependence. A second potential moderator of the gene–

alcohol misuse relationship is the degree to which the subject sample derives froman ethnically homogeneous (Scandinavian countries) vs. ethnically heterogeneous

(United States) population since more homogeneous samples have lower within

group variance and a higher probability of achieving statistical significance than

more heterogeneous samples.[20] The severity of alcohol abuse is a third potential

moderating variable, for some researchers have found that heredity is more

intimately involved in alcohol dependence than alcohol abuse or problem

drinking.[31] The year a study was published is a fourth potential moderator

variable, in part because it correlates significantly with design quality. [32] To

reflect advances taking place in behavior genetic research on alcohol abuse/

dependence in the mid-1980s (e.g., routine use of blood tests for zygosity;

development of criterion definitions and methods that were more structured and

reliable than earlier definitions and methods), 1985 served as the cutting point

for a study’s year of publication.Data for the present meta-analysis were gathered from behavior genetic

(family, twin, adoption) studies on problem drinking and alcohol dependence

in humans. Accordingly, molecular analyses, animal research, studies on

substances other than alcohol, and investigations into alcohol use rather than

misuse were excluded from this meta-analysis. In addition to explaining the

overall gene– alcohol misuse relationship and its breakdown by moderator

variable—gender (male, female), nationality (United States, foreign), pattern

severity (more severe, less severe), and year of publication (before 1985, since

1985)—the present meta-analysis also produced effect sizes for family, twin,

and adoption studies. The null hypothesis held that there would be no rela-

tionship between heredity, as measured by the three behavior genetic methodo-

logies, and alcohol abuse/dependence. In the event the null hypothesis could be

rejected it was reasoned that the gene–alcohol misuse relationship would be

stronger for males, studies conducted outside the United States, samples dis-

playing more severe patterns of alcohol misuse, and investigations published

prior to 1985.

WALTERS560



METHOD

Selection of studies for this meta-analysis began with a computerized

search of the PsycINFO and MEDLINE databases for studies published between

1970 and 2000 in which the following key words served as identifiers: alcohol,

alcoholism, drinking, gene, heredity, family history, pedigree, twin, and adoption.

Additional studies were gleaned from the reference sections of articles identified

by the electronic search. This procedure yielded 50 behavior genetic studies on

alcohol abuse/dependence (22 family studies, 18 twin studies, 10 adoption

studies) and 72 total effect sizes. Several studies employed over-lapping samples

and some investigators reported multiple outcomes for the same group of

individuals. Multiple outcomes are listed only in studies where they provide novel

information (e.g., separate diagnoses of alcohol abuse and dependence) and thenonly as an averaged composite before being combined with other studies. [21,33]

A case-to-case statistical model in the form of a 2 £ 2 table of outcomes,

whereby a phi coefficient was calculated by contrasting abuse status (absent vs.

present) with genetic status (FH þ /MZ/biological parent þ vs. FH 2 /DZ/bio-

logical parent– ), was employed in this meta-analysis of behavior genetic research

on alcohol misuse. Thecase-to-casemodelwas preferredover thecase-to-baserate

model proposed by Gottesman and Carey,[34] in which a tetrachoric coefficient is

calculated, because the case-to-case model allows for direct comparisons of

subjects from the same sample, whether that entails contrasting people with and

without a family history of alcohol abuse/dependence, MZ and DZ twins

concordant and discordant for alcohol abuse/dependence, or adoptees with and

without a history of biological parent alcohol abuse/dependence. It was reasoned

that the case-to-case model more clearly captures the spirit of gene – alcoholmisuse research. Accordingly, only family studies possessing a control or non-

alcohol misusing comparison group are included in this meta-analysis.

The phi coefficients obtained in this study were transformed into Fisher’s z

for the purpose pooling the results of different studies and then backtransformed

into phicoefficients. The minimum, maximum, median, weighted (bysamplesize)

mean, and unweighted mean effect sizes (f ) were calculated, along with the 95%

confidence interval for the weighted mean effect size. The statistical procedures

used to combine studies, test for homogeneity, and compute a 95% confidence

interval were based on the work of Hedges and Olkin.[35] Sampling error was

calculated using the Schmidt–Hunter method —s2e ¼ ð12 r 2Þ 2* k Þ= N —where

r 2 represents the average weighted mean of the effect size, k the number of

studies, and N the total sample size.[36] Fleiss[37] recommends use of the odds

ratio instead of the phi coefficient to summarize categorical effect size data. This

issue is taken up further in the “Discussion” section of this paper.

Additional analyses were calculated using the four moderator variables

of proband gender (male, female), sample nationality (United States, foreign),




pattern severity (more severe, less severe), and year of publication (before 1985,

since 1985). The breakdowns for gender, nationality, and year of publication are

self-evident, while pattern severity was coded less when the alcohol use pattern

was described as abuse or problem drinking and more when the pattern was

diagnosed as alcoholism or alcohol dependence. Samples were considered mixed

if they contained subjects classified as both high and low severity. Gender was

dummy coded using a three-category system (male ¼ 1, both ¼ 2, female ¼ 3),

nationality using a two-category system (United States ¼ 1, foreign or non-

UnitedStates ¼ 2),pattern severity using a three-category system(less severe ¼ 1

mixed ¼ 2, more severe ¼ 3),and year of publication using a two-categorysystem

(before 1985 ¼ 1; since 1985 ¼ 2).

RESULTS

The 50 studies included in this meta-analysis of behavior genetic research

on alcohol misuse are listed in Table 1 (family studies), Table 2 (twin studies),

and Table 3 (adoption studies). Mean phi values of 0.12 (weighted) and 0.15

(unweighted) were found for the entire population of effect sizes ðk ¼ 72; total

N ¼ 58; 887Þ: These values, along with the coefficients attained by family, twin,

and adoption studies, are listed in Table 4. It should be noted, however, that

heterogeneity was high for three groups of pooled effect sizes—all studies,

Q ð71Þ ¼ 253:51; p , 0:001; family studies, Q ð30Þ ¼ 175:27; p , 0:001; and

adoption studies, Q ð10Þ ¼ 38:49; p , 0:001—and low for twin studies—

Q ð29Þ ¼ 40:07; p ¼ 0:08: Consequently, the analyses were broken down further

by moderator variable—i.e., gender (male– female), location (US-foreign),pattern severity (more–less), and publication date (before 1985, since 1985)—

but with only a few exceptions (i.e., US-adoption studies), the heterogeneity of

the effect size estimates for the overall estimate as well as for family and adop-

tion studies remained high.

A multiple regression analysis of the four moderator variables on outcome

(phi coefficients for all effect sizes included in the overall estimate) produced a

multiple correlation of 0.38 and R2 of 0.14. Beta weights for the four moderator

variables that were regressed onto outcome were as follows: gender (20.25),

nationality (20.14), severity (0.24), and year of publication (0.15). Only the

gender and severity betas achieved statistical significance ð p , 0:05Þ: A statistical

breakdown of effect sizes for all studies, family studies, twin studies, and

adoption studies subdivided by moderator variable can be found in Table 5.

In an attempt to identify the upper limit of heritability for alcohol misuse

the 13 (11 twin, 2 adoption) studies with moderating conditions most favorable to

a genetic interpretation of problem drinking (namely, male samples with more

severe diagnoses of alcohol misuse) were analyzed as a group. The outcome

WALTERS562



T a b l e 1 .

F a m i l y S t u d i e s o n A l c o h o l M i s u s e

F a m i l y M e m b e r s

P r o b a n d S u b j e c t s

C o n t r o l S u b j e c t s

D i a g n o s t i c

O u t c o m e ( % ) a

M o d e r a t i n g V a r i a b l e s b

L o c a t i o n

N

S e x

D e s c r i p t i o n

N

S e x


R e l a t i o n

C r i t e r i a

P r o b a n d

C o n t r o l

f

S e x

N a t

S e v

Y P

S o u r c e

S w e d e n

2 0 3

M

I n p t a n d

o u t p t

a l c o h o l i c s

8 5

M

S u r g i c a l p t s

F a t h e r

A l c o h o l a b u s e

w / s o c i a l

c o n s e q u e n c e s

2 6 . 2

3 . 4

0 . 2 6

M

F o r M o r e P r e

[ 5 5 ]

U n i t e d S t a t e s

5 0

M a n d F

I n p t a l c o h o l i c s

f r o m U S

3 0 0

M a n d F

S w i s s s u r g i c a l

a n d p s y c h

p t s

F a t h e r

A l c o h o l i s m

2 2 . 0

9 . 7

0 . 1 4

B

U S

M o r e P r e

[ 5 6 ]


1 8 3

M

A l c o h o l i c s

4 4 1

M a n d F

M o d . d r i n k e r s

a n d n o n -

d r i n k e r s

F a t h e r

A l c o h o l i s m

4 . 9

0 . 0

0 . 1 3

M

U S

M o r e P r e

[ 5 7 ]

2 4

F

A l c o h o l i c s

6 6 2

F

M o d . d r i n k

e r s

a n d n o n -

d r i n k e r s

F a t h e r

A l c o h o l i s m

4 . 2

1 . 2

0 . 0 5

F

U S

M o r e P r e


5 0 0

M a n d F


2 3 0

M a n d F

H o s p i t a l

e m p l o y e

e

c o n t r o l s

P a r e n t s

A l c o h o l i s m

2 7 . 6

0 . 9

0 . 3 2

B

U S

M o r e P r e

[ 5 8 ]

C a n a d a

5 6

M a n d F


9 4 4

M a n d F

I n p t w i t h n

o n -

a l c o h o l

a b u s e d x

F a t h e r

E x c e s s i v e

a l c o h o l

c o n s u m p t i o n

2 3 . 2

1 0 . 0

0 . 1 0

B

F o r M o r e P r e

[ 5 9 ]


6 2

M a n d F


6 0 8

M a n d F

P t s w / m e d i c a l

o r a f f e c t i v e

d i s o r d e r

d x

F a t h e r

H o s p i t a l i z a t i o n ;

n e g . c o n s -

e q u e n c e s f r o m

d r i n k i n g

1 6 . 1

6 . 2

0 . 1 1

B

U S

M o r e P r e

[ 6 0 ]

( c o n t i n u e d )




T a b l e 1 .

C o n t i n u e d




D i a g n o s t i c

O u t c o m e ( % ) a

M o d e r a t i n g V a r i a b l e s b

L o c a t i o n

N

S e x


N

S e x


R e l a t i o n

C r i t e r i a

P r o b a n d

C o n t r o l

f

S e x

N a t

S e v

Y P

S o u r c e

U n i t e d K i n g d o m

4 0

M

A l c o h o l i c s

4 0

M

P t s w i t h

p h y s i c a l

i l l n e s s

u n r e l a t e d

t o a l c o h o l

F a t h e r

A l c o h o l a d d i c t i o n ;

h o s p i t a l i z a t i o n ;

w i t h d r a w a l

s y m p t o m s

2 . 5

2 . 5

0 . 0 0

M

F o r M o r e P r e

[ 6 1 ]


5 6

F


5 6

F

N o n a l c o h o

l i c

d r u g

a b u s e r s

F a t h e r

H e a v y

d r i n k i n g

4 6 . 4

1 2 . 5

0 . 3 7

F

U S

M o r e P r e

[ 6 2 ]


3 2

M a n d F

A l c o h o l i c

h a l f -

s i b l i n g s

1 3 2

M a n d F

N o n a l c o h o

l i c

h a l f -

s i b l i n g s

P a r e n t s

A l c o h o l i s m

6 2 . 0

2 0 . 0

0 . 3 8

B

U S

M o r e P r e

[ 6 3 ]


5 1

M


7

M

I n p t p s y c h

c o n t r o l s

1 s t d e g r e e

A l c o h o l i c

d r i n k i n g s t y l e

5 6 . 8

2 8 . 6

0 . 1 8

M

U S

M o r e P r e

[ 1 5 ]

3 2

F


3 2

F

I n p t p s y c h

c o n t r o l s

1 s t d e g r e e

A l c o h o l i c

d r i n k i n g s t y l e

5 9 . 4

5 0 . 0

0 . 0 9

F

U S

M o r e P r e


3 9

M

D e p e n d e n t

p r o b

d r i n k i n g

7 2 3

M a n d F

N o n a l c o h o

l

a b u s e r s

P a r e n t s

A l c o h o l i s m / p r o b l e m

d r i n k i n g

3 0 . 8

1 0 . 6

0 . 1 4

M

U S

M o r e P o s t

[ 6 4 ]

2 1

F

D e p e n d e n t

p r o b

d r i n k i n g

9 8 9

F

N o n a l c o h o

l

a b u s e r s

P a r e n t s

A l c o h o l i s m / p r o b l e m

d r i n k i n g

2 3 . 8

1 7 . 9

0 . 0 2

F

U S

M o r e P o s t


7 2

M a n d F

A l c o h o l

a b u s i n g

a d o l

1 2 7 7

M a n d F

N o n a l c o h o

l

a b u s i n g

a d o l

1 s t a n d

2 n d d e g r e e

A l c o h o l i s m

4 0 . 3

2 2 . 5

0 . 0 9

B

U S

L e s s

P o s t

[ 6 5 ]


1 6 6

M

D S M - I I I

a l c o h o l

a b u s e / d e p

4 5 5

M

N o n a l c o h o

l

a b u s e r s

P a r e n t s


o r d e p e n d e n c e

3 6 . 1

2 0 . 4

0 . 1 6

M

U S

M i x

P o s t

[ 6 6 ]

WALTERS564



6 7

F

D S M - I I I

a l c o h o l

a b u s e / d e p

9 7 1

F

N o n a l c o h o

l

a b u s e r s

P a r e n t s



5 0 . 7

2 4 . 0

0 . 1 5

F

U S

M i x

P o s t


6 0

M a n d F

D S M - I I I

a l c o h o l

a b u s e / d e p

1 5 9

M a n d F

N o n a l c o h o

l

a b u s e r s

P a r e n t s

A l c o h o l i s m

6 5 . 0

5 7 . 9

0 . 0 6

B

U S

M i x

P o s t

[ 4 8 ]


8 9

M a n d F

O u t p t p r o b l e m

d r i n k e r s

8 3

M a n d F

N o n p r o b l e m

d r i n k e r s

1 s t a n d

2 n d d e g r e e

P r o b l e m

d r i n k i n g

5 5 . 1

1 6 . 9

0 . 4 0

B

F o r L e s s

P o s t

[ 6 7 ]


3 3 8

M a n d F

D S M - I I I

a l c o h o l

a b u s e / d e p

2 1 3 5

M a n d F

N o n a l c o h o

l

a b u s e r s

1 s t d e g r e e

A l c o h o l i s m

3 1 . 6

1 7 . 0

0 . 1 3

B

U S

M i x

P o s t

[ 6 8 ]


2 8 0 6

M a n d F

D S M - I I I - R

a l c o h o l

d e p

2 0 , 3 4 6

M a n d F

N o n a l c o h o

l

a b u s e r s

1 s t d e g r e e

A l c o h o l i s m o r

p r o b l e m d r i n k i n g

3 2 . 9

2 1 . 8

0 . 0 9

B

U S

M o r e P o s t

[ 6 9 ]

D e n m a r k

4 9

M

D S M - I I I - R

a l c o h o l

a b u s e

1 8 2

M

N o n a l c o h o

l

a b u s e r s

P a r e n t s

T r e a t m e n t f o r

a l c o h o l i s m

7 3 . 5

6 2 . 7

0 . 1 0

M

F o r L e s s

P o s t

[ 7 0 ]

3 9

M

D S M - I I I - R

a l c o h o l

d e p

1 8 2

M

N o n a l c o h o

l

a b u s e r s

P a r e n t s

T r e a t m e n t o f

a l c o h o l i s m

7 6 . 9

6 2 . 7

0 . 1 2

M

F o r M o r e P o s t

G e r m a n y

6 6

M

I n p a t i e n t s

w / a l c o h o l -

i s m d x

6 4

M

I n p a t i e n t s

w / d e p r e s -

s i o n d x

1 s t d e g r e e

A l c o h o l i s m

8 1 . 2

3 2 . 8

0 . 5 0

M


[ 4 3 ]

3 8

F

I n p a t i e n t s

w / a l c o h o l -

i s m d x

9 6

F

I n p a t i e n t s

w / d e p r e s -

s i o n d x

1 s t d e g r e e

A l c o h o l i s m

4 2 . 1

2 4 . 0

0 . 1 8

F



3 8

M

D S M - I I I - R

a l c o h o l

a b u s e

2 4 7

M

N o n a l c o h o

l

a b u s e r s

1 s t a n d

2 n d d e g r e e

F a t h e r þ

a n o t h e r

1 s t o r 2 n d d e g r e e

a l c o h o l

a b u s e / d e p

7 1 . 0

4 4 . 5

0 . 1 8

M

U S

L e s s

P o s t

[ 7 1 ]

( c o n t i n u e d )




T a b l e 1 .

C o n t i n u e d




D i a g n o s t i c

O u t c o m e ( % ) a

M o d e r a t i n g V a r i a b l e s

b

L o c a t i o n

N

S e x


N

S e x


R e l a t i o n

C r i t e r i a

P r o b a n d

C o n t r o l

f

S e x

N a t

S e v

Y P

S o u r c e

7 3

M

D S M - I I I - R

a l c o h o l

d e p

2 4 7

M

N o n a l c o h o

l

a b u s e r s

1 s t a n d

2 n d d e g r e e

F a t h e r þ

a n o t h e r

1 s t o r 2 n d

d e g r e e a l c o h o l

a b u s e / d e p

7 5 . 3

4 4 . 5

0 . 2 6

M

U S

M o r e P o s t


9 1 6

M

D S M - I I I - R

a l c o h o l

d e p

1 1 1

M

N o n a l c o h o

l

a b u s e r s

1 s t

d e g r e e

A l c o h o l

d e p e n d e n c e

4 9 . 7

1 9 . 8

0 . 1 7

M

U S

M o r e P o s t

[ 7 2 ]

2 9 6

F

D S M - I I I R

a l c o h o l

d e p

1 0 6

F

N o n a l c o h o

l

a b u s e r s

1 s t

d e g r e e

A l c o h o l

d e p e n d e n c e

2 3 . 8

6 . 0

0 . 1 2

F

U S

M o r e P o s t


6 4 0

M

D S M - I I I - R

a l c o h o l

d e p

3 4 3

M

N o n a l c o h o

l

a b u s e r s

1 s t

d e g r e e



4 5 . 6

1 9 . 8

0 . 2 6

M

U S

M o r e P o s t

[ 5 3 ]

1 6 6

F

D S M - I I I - R

a l c o h o l

d e p

2 4 5

F

N o n a l c o h o

l

a b u s e r s

1 s t

d e g r e e



5 2 . 4

2 0 . 4

0 . 3 3

F

U S

M o r e P o s t

N o t e : a d o l ¼ a

d o l e s c e n t ; d e p ¼

d e p e n d e n c e ; d i s ¼

d i s o r d e r ; d x ¼

d i a g n o s i s ; i n p t ¼

i n p a t i e n t ; n e g ¼

n e g a t i v e ;

o u t p t ¼

o u t p a t i e n t ; p r o b ¼

p r o b l e m ; p s y c h ¼

p s y c h i a t r i c ; p t s

¼

p a t i e n t s .

a

O u t c o m e i s t h e p e r c e n t a g e o f p r o b a n d ( a l c o h o l a b u s i n g ) a n d c o n t r o l ( n o n a l c o h o l a b u s i n g ) s u b j e c t s w i t h a f a m i l y h i s t o r y o f a l c o h o l a b u s e , f a m i l y b e i n g d e fi n e d u n d e r

r e l a t i o n a n d a l c

o h o l a b u s e b e i n g d e fi n e d u n d e r d i a g n o s t i c c r i t e r i a .

b

M o d e r a t i n g v a r i a b l e s : p r o b a n d s e x o r g e n d e r ( M ¼

m a l e , F ¼

f e m a l e , B ¼

b o t h ) ; p r o b a n d n a t i o n a l i t y ( U S ¼

U n i t e d S t a t e s , F o r ¼

f o r e i g n o r o u t s i d e t h e U n i t e d

S t a t e s ) , S e v ¼

s e v e r i t y o f a l c o h o l a b u s e i n p r o b a n d s u b j e c t s ( M o r e ¼

m o r e s e v e r e , L e s s ¼

l e s s s e v e r e , M i x ¼ m i x t u r e o f h i g h a n d l o w s e v e r i t y ) , Y P ¼

y e a r o f

p u b l i c a t i o n ( P r e ¼

b e f o r e 1 9 8 5 , P o s t ¼

s i n c e 1 9 8 5 ) .

WALTERS566



T a b l e 2 .

T w i n S t u d i e s o n A l c o h o l M i s u s e

M Z T w i n s

D Z T w i n s

M o d e r a t i n g V a r i a b l e s a

L o c a t i o n

D i a g n o s t i c C r i t e r i a

N b

S e x

C o n c o r d c

N b

S e x

C o n c o r d c

f

S e x

N a t

S e v

Y P

S o u r c e

S w e d e n

A l c o h o l A b u s e

5 8

M

5 4 . 0

1 3 8

M

2 8 . 0

0 . 2 4

M

F o r

L e s s

P r e

[ 7 3 ]

C h r o n i c A l c o h o l i s m

2 7

M

7 1 . 0

6 0

M

3 2 . 0

0 . 3 6

M

F o r

M o r e

P r e

F i n l a n d

A l c o h o l i s m

1 7 2

M

2 6 . 0

5 5 7

M

1 2 . 0

0 . 1 5

M

F o r

M o r e

P r e

[ 7 4 ]

H e a v y A l c o h o l U s e

1 9 8

M

7 5 . 0

6 4 1

M

6 3 . 0

0 . 0 2

M

F o r

L e s s

P r e

S w e d e n

A l c o h o l i s m

( 7 5 0 ) d

M a n d F

2 2 . 0

M a n d F

1 6 . 0

0 . 0 8

B

F o r

M o r e

P r e

[ 7 5 ]


A l c o h o l i s m

1 5

M

3 3 . 0

2 0

M

3 0 . 0

0 . 0 4

M

F o r

M o r e

P r e

[ 7 6 ]

1 3

F

8 . 0

8

F

1 3 . 0

2 0

. 0 8

F

F o r

M o r e

P r e


A l c o h o l i s m

2 7 1

M

2 6 . 3

4 4 4

M

1 1 . 9

0 . 1 8

M

U S

M o r e

P r e

[ 7 7 ]

F i n i s h T w i n C o

h o r t

F i n l a n d

A l c o h o l i s m

6 9

M

1 3 . 0

1 7 5

M

5 . 7

0 . 1 2

M

F o r

M o r e

P r e

[ 7 8 ]

7

F

0 . 0

2 0

F

0 . 0

0 . 0 0

F

F o r

M o r e

P r e

F i n l a n d

B r o a d d e fi n i t i o n o f

a l c o h o l a b u s e

6 4

M

1 0 . 9

1 8 6

M

6 . 4

0 . 0 7

M

F o r

L e s s

P o s t

[ 7 9 ]

S w e d i s h T w i n R e g i s t r y I

S w e d e n

A l c o h o l i s m

9 5

M

1 2 . 6

1 8 7

M

9 . 1

0 . 0 7

M

F o r

M o r e

P o s t

[ 8 0 ]

M i n n e s o t a T w i n R e g i s t r y


D S M - I I I A l c o h o l

A b u s e

5 0

M

7 4 . 0

6 4

M

5 7 . 8

0 . 1 7

M

U S

L e s s

P o s t

[ 4 4 ]


D e p

3 9

M

5 9 . 0

4 7

M

3 6 . 2

0 . 2 3

M

U S

M o r e

P o s t


A b u s e

3 0

F

2 6 . 7

2 2

F

2 7 . 3

2 0

. 0 1

F

U S

L e s s

P o s t


D e p

2 4

F

2 5 . 0

2 0

F

5 . 0

0 . 2 7

F

U S

M o r e

P o s t ( c

o n t i n u e d )




T a b l e 2 .

C o n t i n u e d

M Z T w i n s

D Z T w i n s


L o c a t i o n


N b

S e x

C o n c o r d c

N b

S e x

C o n c o r d c

f

S e x

N a t

S e v

Y P

S o u r c e


C l o n i n g e r T y p e I

5 4

M

4 8 . 1

6 5

M

3 2 . 3

0 . 1 6

M

U S

L e s s

P o s t

[ 3 3 ]

C l o n i n g e r T y p e I I

5 4

M

5 7 . 4

6 5

M

3 2 . 3

0 . 2 5

M

U S

M o r e

P o s t

V i r g i n i a T w i n R e g i s t r y


A l c o h o l D e p e n d e n c e

2 0 3

F

2 6 . 2

1 5 4

F

1 1 . 9

0 . 1 7

F

U S

M o r e

P o s t

[ 1 6 ]

P r o b l e m D r i n k i n g

7 3

F

4 6 . 9

5 5

F

3 1 . 5

0 . 1 6

F

U S

L e s s

P o s t


D S M - I V A l c o h o l

A b u s e

5 0 5

M

4 0 . 0

3 1 6

M

2 9 . 8

0 . 1 1

M

U S

L e s s

P o s t

[ 8 1 ]

D S M - I V A l c o h o l

D e p

3 7 8

M

3 1 . 7

4 3 6

M

1 9 . 3

0 . 1 4

M

U S

M o r e

P o s t

V o l u n t e e r T w i n

S a m p l e



4 2

M

2 8 . 6

1 2

M

8 . 3

0 . 2 0

M

U S

L e s s

P o s t

[ 4 5 ]


6 3

F

1 1 . 1

2 4

F

8 . 3

0 . 0 4

F

U S

L e s s

P o s t

A u s t r a l i a n T w i n R e g i s t r y

A u s t r a l i a


3 9 6

M

3 8 . 9

2 3 1

M

1 9 . 9

0 . 2 0

M

F o r

M o r e

P o s t

[ 4 1 ]


9 3 2

F

2 0 . 9

5 3 4

F

9 . 2

0 . 1 1

F

F o r

M o r e

P o s t

WALTERS568



S w e d i s h T w i n R e g i s t r y I I

S w e d e n

T e m p e r a n c e B o a r d

R e g i s t r a t i o n

7 5 3

M

3 1 . 3

1 2 0 9

M

2 1 . 6

0 . 1 1

M

F o r

L e s s

P o s t

[ 8 2 ]

W o r l d W a r I I T

w i n R e g i s t r y


H e a v y a l c o h o l

C o n s u m p t i o n

7 0 9

M

2 8 . 6

8 4 2

M

2 1 . 1

0 . 0 9

M

U S

L e s s

P o s t

[ 8 3 ]

V i e t n a m E r a T w i n R e g i s t r y


A l c o h o l i s m

7 1 0

M

5 3 . 2

5 8 8

M

4 3 . 2

0 . 1 0

M

U S

M o r e

P o s t

[ 8 4 ]

C a n a d i a n T w i n

R e g i s t r y

C a n a d a

A l c o h o l M i s u s e

1 3 1

M

7 4 . 0

7 6

M

5 2 . 6

0 . 2 2

M

F o r

L e s s

P o s t

[ 5 4 ]

2 1 5

F

6 7 . 0

1 7 5

F

6 0 . 0

0 . 0 7

F

F o r

L e s s

P o s t

a


m a l e , F ¼ f

e m a l e , B ¼




S t a t e s ) , S e v ¼




y e a r o f

p u b l i c a t i o n ( P r e

¼

b e f o r e 1 9 8 5 , P o s t ¼

s i n c e 1 9 8 5 ) .

b

N u m b e r o f t w

i n p a i r s .

c

P a i r - w i s e c o n c o r d a n c e f o r a l c o h o l a b u s e .

d

T h e a u t h o r s o

f t h i s s t u d y f a i l e d t o s p e c i f y t h e n u m b e r o f M Z a n d D Z t w i n s c o m p l e t i n g q u e s t i o n n a i r e s o n a l c o h

o l u s e a n d a b u s e p a t t e r n s b u t d i d i n d i c a t e t h a t

a p p r o x i m a t e l y 1 5 0 0 p a i r s o f t w i n s w e r e s e n t q u e s t i o n n a i r e s . G i v e

n a 5 0 % r a t e o f r e t u r n o f m a i l e d q u e s t i o n n a i r e s i t

i s e s t i m a t e d t h a t a p p r o x i m a t e l y 7 5 0 t w i n p a i r s

p a r t i c i p a t e d i n t h i s s t u d y . T h e p h i w a s c a l c u l a t e d f r o m t h e p e r c e n t

a g e s g i v e n b y t h e a u t h o r s a n d a n N o f 7 5 0 w a s u s e

d t o p o o l t h e s e d a t a w i t h o t h e r t w i n a n d g e n e t i c

s t u d i e s i n t h e d e r i v a t i o n o f a w e i g h t e d m e a n f .

S R ¼

s e l f r e p o r t .




T a b l e 3 .

A d o p t i o n S t u d i e s o n A l c o h o l M i s u s e




L o c a t i o n


N

S e x

O u t c o m e b

N

S e x

O u t c o m e b

f

S e x

N a t

S e v

Y P

S o u r c e



2 7

M a n d F

3 . 7

2 2

M a n d F

4 . 5

2

0 . 0 2

B

U S

L e s s

P r e

[ 8 5 ]

D a n i s h A d o p t i o

n C o h o r t

D e n m a r k

A l c o h o l i s m

5 5

M

1 8 . 2

7 8

M

5 . 1

0 . 2 1

M

F o r

M o r e

P r e

[ 2 1 ]

P r o b l e m d r i n k i n g

5 5

M

9 . 1

7 8

M

1 4 . 1

2

0 . 0 8

M

F o r

L e s s

P r e

D e n m a r k

A l c o h o l i s m

6

F

3 3 . 3

9 0

F

5 2 . 2

2

0 . 0 9

F

F o r

M o r e

P r e

[ 2 2 ]

S t o c k h o l m A d o

p t i o n S t u d y

S w e d e n


8 9

M

3 9 . 4

8 9 2

M

1 3 . 1

0 . 2 1

M

F o r

L e s s

P r e

[ 8 6 ]

S w e d e n


1 7 2

F

7 . 0

7 4 1

F

2 . 6

0 . 1 0

F

F o r

L e s s

P r e

[ 2 4 ]

S w e d e n

S e v e r e a l c o h o l a b u s e

3 0 7

M

7 . 8

5 5 5

M

4 . 9

0 . 0 6

M

F o r

L e s s

P r e

[ 8 7 ]

S w e d e n


1 0 8

M

2 4 . 1

4 6 9

M

1 2 . 8

0 . 1 2

M

F o r

L e s s

P o s t

[ 2 5 ]

1 1 4

F

0 . 9

5 4 6

F

1 . 3

2

0 . 0 1

F

F o r

L e s s

P o s t

I o w a A d o p t i o n

C o h o r t


A l c o h o l i s m

2 3

M

1 3 . 0

6 9

M

1 . 4

0 . 2 6

M

U S

M o r e

P r e

[ 2 7 ]



3 9

M a n d F

4 8 . 7

4 0 4

M a n d F

1 3 . 9

0 . 2 5

B

U S

L e s s

P o s t

[ 2 8 ]



4 9

M a n d F

7 0 . 6

3 4

M a n d F

5 5 . 1

0 . 1 6

B

U S

L e s s

P o s t

[ 8 8 ]

a


m a l e , F ¼ f

e m a l e , B ¼




S t a t e s ) , S e v ¼




y e a r o f

p u b l i c a t i o n ( P r e ¼

b e f o r e 1 9 8 5 , P o s t ¼

s i n c e 1 9 8 5 ) .

b

P e r c e n t o f p r o

b a n d ( a l c o h o l a b u s i n g ) a n d c o n t r o l ( n o n a l c o h o l a b

u s i n g ) a d o p t e e s w i t h a t l e a s t o n e a l c o h o l a b u s i n g

b i o l o g i c a l p a r e n t .

WALTERS570



of this restricted analysis revealed a weighted mean f of 0.15 (95% confidence

interval ¼ 0.12– 0.18) and unweighted mean f of 0.18 (95% confidence

interval ¼ 0.15– 0.21) in a sample of homogeneous effect sizes, Q ð12Þ ¼ 15:67; p . 0:10: Heritability is calculated by doubling the mean effect size estimates of

a correlational measure like the phi coefficient. This results in heritability

estimates of 30% (weighted) and 36% (unweighted) for males with severe

alcohol dependence, which is somewhat higher than the 20–26% heritability

suggested by the full sample of twin and adoption studies.

DISCUSSION

The outcome of this meta-analysis paints a somewhat different picture than

the one drawn by the more enthusiastic proponents of the genetic view of alcohol

misuse (Cloninger in Refs. [13,38,39]). The heritability of alcohol misuse, which

can be estimated by doubling the effect sizes attained in the present meta-analysis

by all twin and adoption studies, appears to range between 20 and 26%. Even

when the analyses are restricted to studies most favorable to the genetic

hypothesis—i.e., males diagnosed with severe forms of alcohol dependence—

heritability does not appear to exceed 30–36%, which is somewhat lower than

the 40–60% rate normally cited in the literature. Therefore, Wilson and

Crowe’s[40] quandary over whether we should identify people at risk for alcohol

misuse for preventative purposes is deemed moot to the extent that the gene–

alcohol misuse relationship is probably too weak and variable to permit reliable

identification. Our limited time, energy, and financial resources might therefore

be better spent clarifying the boundaries and parameters of this relationship than

metaphorically spinning our wheels searching for phantom “alcoholism genes”

independent of their environmental context.

Table 4. Effect Sizes for Studies on Alcohol Misuse

Overall Effect Family Studies

Twin

Studies

Adoption

Studies

Number of f estimates 72 31 30 11

Maximum f 0.50 0.50 0.36 0.26

Median f 0.13 0.14 0.12 0.11

Minimum f 20.09 0.00 20.08 20.09

Unweighted mean (f ) 0.15 0.18 0.13 0.10

Weighted mean (f ) 0.12 0.12 0.12 0.12

95% Confidence intervala 0.11 – 0.12 0.11 – 0.13 0.10 – 0.13 0.09 – 0.14

a Calculated from the weighted mean f and standard error of the weighted mean.




T a b l e 5 .

E f f e c t s o f M o d e r a t o r V a r i a b l e s o n t h e G e n e s – A l c o h o l M i s u s

e R e l a t i o n s h i p

P r o b a n d G e n d e r

N a t i o n a l i t y

P a t t e r n

S e v e r i t y

Y e a r o f P u b l i c a t i o n

M a l e

F e m a l e

U S

F o r e i g n

M o r e

L e s s

P r e - 8 5

P o s t - 8 5

O v e r a l l e f f e c t

N u m b e r o f f

e s t i m a t e s

3 8

2 0

4 1

3 1

4 3

2 7

2 9

4 3

M a x i m u m f

0 . 5 0

0 . 3 7

0 . 3 8

0 . 5 0

0 . 5 0

0 . 4 0

0 . 3 8

0 . 5 0

M e d i a n f

0 . 1 5

0 . 1 0

0 . 1 6

0 . 0 9

0 . 1 4

0 . 1 1

0 . 1 1

0 . 1 4

M i n i m u m f

0 . 0 0

2

0 . 0 9

2

0 . 0 2

2

0 . 0 9

2

0 . 0 9

2

0 . 0 8

2

0 . 0 9

2

0 . 0 1

U n w e i g h t e d

m e a n ( f )

0 . 1 6

0 . 1 0

0 . 1 6

0 . 1 3

0 . 1 7

0 . 1 2

0 . 1 3

0 . 1 6

W e i g h t e d m

e a n ( f )

0 . 1 4

0 . 1 0

0 . 1 2

0 . 1 2

0 . 1 2

0 . 1 1

0 . 1 4

0 . 1 1

9 5 % C o n fi d e n c e

i n t e r v a l a

0 . 1 3 – 0 . 1 6

0 . 0 8 – 0 . 1 2

0 . 1 1 – 0 . 1 3

0 . 1 0 – 0 . 1 3

0 . 1 1 – 0 . 1 3

0 . 0 9 – 0 . 1 3

0 . 1 2 – 0 . 1 5

0 . 1 0 – 0 . 1 2

F a m i l y S t u d i e s

N u m b e r o f f

e s t i m a t e s

1 3

8

2 3

8

2 3

4

1 2

1 9

M a x i m u m f

0 . 5 0

0 . 3 7

0 . 3 8

0 . 5 0

0 . 5 0

0 . 4 0

0 . 3 8

0 . 5 0

M e d i a n f

0 . 1 7

0 . 1 4

0 . 1 4

0 . 1 5

0 . 1 4

0 . 1 4

0 . 1 4

0 . 1 5

M i n i m u m f

0 . 0 0

0 . 0 2

0 . 0 2

0 . 0 0

0 . 0 0

0 . 0 9

0 . 0 0

0 . 0 2

U n w e i g h t e d

m e a n ( f )

0 . 1 9

0 . 1 7

0 . 1 7

0 . 2 1

0 . 1 9

0 . 2 0

0 . 1 8

0 . 1 8

W e i g h t e d m

e a n ( f )

0 . 1 9

0 . 1 2

0 . 1 1

0 . 1 7

0 . 1 1

0 . 1 3

0 . 1 6

0 . 1 1


i n t e r v a l a

0 . 1 6 – 0 . 2 1

0 . 0 9 – 0 . 1 5

0 . 1 0 – 0 . 1 2

0 . 1 3 – 0 . 2 1

0 . 1 0 – 0 . 1 2

0 . 0 9 – 0 . 1 8

0 . 1 3 – 0 . 1 9

0 . 1 0 – 1 2

WALTERS572



T w i n s t u d i e s

N u m b e r o f f

e s t i m a t e s

2 0

9

1 4

1 6

1 7

1 3

1 0

2 0

M a x i m u m f

0 . 3 6

0 . 2 7

0 . 2 7

0 . 3 6

0 . 3 6

0 . 2 4

0 . 3 6

0 . 2 7

M e d i a n f

0 . 1 4

0 . 0 7

0 . 1 6

0 . 1 1

0 . 1 4

0 . 1 1

0 . 1 0

0 . 1 4

M i n i m u m f

0 . 0 2

2

0 . 0 8

2

0 . 0 1

2

0 . 0 8

2

0 . 0 8

2

0 . 0 1

2

0 . 0 8

2

0 . 0 1

U n w e i g h t e d

m e a n ( f )

0 . 1 5

0 . 0 8

0 . 1 5

0 . 1 1

0 . 1 4

0 . 1 2

0 . 1 1

0 . 1 4

W e i g h t e d m

e a n ( f )

0 . 1 2

0 . 1 1

0 . 1 2

0 . 1 1

0 . 1 3

0 . 1 0

0 . 1 2

0 . 1 2


i n t e r v a l a

0 . 1 0 – 0 . 1 4

0 . 0 7 – 0 . 1 8

0 . 1 0 – 0 . 1 5

0 . 0 9 – 0 . 1 3

0 . 1 1 – 0 . 1 6

0 . 0 8 – 0 . 1 2

0 . 0 8 – 0 . 1 5

0 . 1 0 – 0 . 1 4

A d o p t i o n s t u d i e s

N u m b e r o f f

e s t i m a t e s

5

3

4

7

3

9

7

4

M a x i m u m f

0 . 2 6

0 . 1 0

0 . 2 6

0 . 2 1

0 . 2 6

0 . 2 5

0 . 2 6

0 . 2 5

M e d i a n f

0 . 1 2

2

0 . 0 1

0 . 2 0

0 . 0 6

0 . 2 1

0 . 1 0

0 . 0 6

0 . 1 4

M i n i m u m f

0 . 0 6

2

0 . 0 9

2

0 . 0 2

2

0 . 0 9

2

0 . 0 9

2

0 . 0 8

2

0 . 0 9

2

0 . 0 1

U n w e i g h t e d

m e a n ( f )

0 . 1 4

2

0 . 0 0

0 . 1 6

0 . 0 6

0 . 1 3

0 . 0 9

0 . 0 8

0 . 1 3

W e i g h t e d m

e a n ( f )

0 . 1 4

0 . 0 4

0 . 2 2

0 . 1 0

0 . 1 4

0 . 1 1

0 . 1 2

0 . 1 1


i n t e r v a l a

0 . 1 0 2

0 . 1 7

2

0 . 0 0 – 0 . 0 9

0 . 1 5 – 0 . 2 9

0 . 0 7 – 0 . 1 3

0 . 0 3 – 0 . 2 4

0 . 0 8 – 0 . 1 4

0 . 0 8 – 0 . 1 5

0 . 0 6 – 0 . 1 5

a

C a l c u l a t e d f r o m t h e w e i g h t e d m e a n f

a n d s t a n d a r d e r r o r o f

t h e w e i g h t e d m e a n .




Four potential moderator variables were examined in this study: proband

gender, sample nationality, pattern severity, and year of publication. Congruent

with a number of individual studies in which male and female probands have been

compared,[25,41– 45] the heritability of alcohol misuse was stronger in males than

females. While this may reflect a genuine male–female difference in genetic

liability for alcohol misuse as represented by Cloninger’[46] Type II or male-

limited alcoholism pattern, many of the comparisons involving females suffered

from low power due to small sample sizes and decreased rates of alcohol misuse

compared to males. When analyses were restricted to female studies with sample

sizes larger than 100 ðk ¼ 13Þ the weighted effect size rose slightly (0.10–0.11)

and the unweighted effect size showed moderate improvement (from 0.10 to 0.14),

both figures of which approach the effect sizes attained for males in this meta-

analysis. These findings lend support to Heath’s[39]

assertion that thegene– alcoholmisuse association may be as strong and consistent in women as it is in men.

There is evidence from the results of this meta-analysis that the severity of

alcohol abuse may moderate the gene–alcohol misuse relationship. One might

be tempted to conclude from this that there are two types of alcohol misuse, one

which is more severe and genetically influenced and the other which is less

severe and mediated principally by environmental factors. These two patterns

conform in a general way to Cloninger’s[46] Type II (male-limited) and Type I

(milieu-limited) categories of alcohol misuse, respectively. However, the pre-

sent findings are also compatible with a continuum view of alcohol misuse in

which the continuum extends from mild to severe alcohol misuse and where

genetic contributions vary both quantitatively and qualitatively at different

points along the continuum. In contrasting the dichotomy and continuum views

on the gene–alcohol misuse relationship we would be well advised to keep inmind that while the difference in effect sizes for studies using more and less

severe definitions of alcohol misuse was modest to moderate, the confidence

intervals for more and less severe definitions of alcohol misuse overlap signi-

ficantly (Table 5).

The third and fourth moderating variables examined in this meta-analysis

(sample nationality, date of publication) had little appreciable effect on the results

obtained by this study. This is good news for supporters of the genetic perspective

on alcohol misuse for two reasons. Firstly, it confirms that the gene–alcohol

misuse relationship is not restricted to ethnically homogeneous populations for it

was just as likely to surface in a culturally diverse culture like the United States as

it was in more ethnically homogeneous cultures such as those found in the

Scandinavian countries. Secondly, a significant genetic effect is just as likely to

occur in more recently published and presumably, more methodologically sound

investigations as it is to appear in earlier and less methodologically rigorous

studies. This second finding certifies that the gene– alcohol misuse correlation is

not simply an artifact of poor quality research designs.

WALTERS574



Overall, the four moderator variables accounted for only 14% of the

variance in the effect sizes procured from this meta-analysis. This indicates that

much of the heterogeneity in the gene– alcohol misuse relationship remains

unexplained. Measurement error and interactions leading to nonshared environ-

mental effects may account for a substantial portion of the heterogeneity in effect

sizes. What variance remains once measurement error and nonshared environ-

mental experience are extracted from the equation is probably attributable to

variables that have not been routinely investigated in behavior genetic research

on alcohol misuse. Either way, a great deal more research is required before we

are in a position to offer firm conclusions as to the relationship between here-

dity and alcohol misuse. If the relative modesty of the effect sizes revealed in this

meta-analysis is not enough to discourage simplistic genetic interpretations of

alcohol misuse then the heterogeneity witnessed between the different studiesshould send a clear message of caution to even the most ardent of genetic

reductionists.

Comparing the present findings with outcomes registered in an earlier

meta-analysis of crime studies[32] reveals that the gene – alcohol misuse relation-

ship is no stronger, and is actually weaker for five of the six family, twin, and

adoption contrasts (the weighted effect size for adoption studies being the one

exception), than the gene–crime relationship (see Fig. 1). These findings insinu-

ate that crime may be as strongly genetic as alcohol abuse. Other results denote

that a portion of the variance traditionally ascribed to genetic differences in alco-

hol abuse may actually be a function of genetic differences in crime. Besides

Cloninger’s[46] observation that the fathers of Type II alcoholics own more

extensive records of prior criminality than the fathers of persons exhibiting the

less genetically influenced Type I pattern, Cadoret and Gath[47] ascertained thatchildhood conduct disorder predicted later alcohol misuse in adoptees and cor-

related, albeit nonsignificantly, with biological parent alcohol misuse. Further-

more, Stabenau[48] determined that a diagnosis of antisocial personality disorder

achieved a three-fold increase in liability for alcohol abuse, doubling the con-

tributions of male gender and a family history of alcohol misuse in predicting

personal misuse of alcohol.

In interpreting the results of the present meta-analysis it should be kept

in mind that the case-to-case method upon which the current analyses were based

possesses less statistical power than the multivariate and model testing procedures

used in many of the individual studies. However, multivariate and model testing

procedures also tend to capitalize on large sample sizes, whereas the case-to-case

approach provides a more equitable and conservative estimate of the gene –

behavior relationship.[49] This may explain why the heritability estimates from

this meta-analysis were lower than anticipated and may even slightly under-

estimate the gene–alcohol misuse relationship. Nevertheless, the case-to-case

method permits inclusion of many more studies than could be accommodated




by multivariate or model testing procedures. By providing a statistic common to

all three behavior genetic methodologies, the case-to-case approach furnishes a

procedure by which family, twin, and adoption studies can be combined and

compared. Despite its inclusiveness, the case-to-case method cannot encompass

every relevant study. As such, individual studies not covered in this meta-analysis

and excluded analyses from some of the studies included in the meta-analysis

should be considered alongside the present meta-analytic results as part of a

comprehensive evaluation of the proposed gene–alcohol misuse relationship.

One such study was an investigation by Vernon et al.[50] in which the social

learning concept of alcohol expectancies was found to be influenced by genetic

factors, suggesting that heredity may be involved in alcohol misuse in a number of

subtle and intricate ways.

Advocates of the twin method will probably take issue with the fact that

pair-wise rather than proband-wise concordance was used to calculate the effect

Figure 1. A Comparison of Effect Sizes for Crime and Alcohol Misuse.

WALTERS576



sizes for the twin study portion of this meta-analysis. However, the pair-wise

method (concordant twin pairs/concordant twins pairs þ discordant twin pairs)

seems more consistent with the way in which family and adoption study data

were analyzed in this meta-analysis than the proband-wise method (2 £

concordant twin pairs/[2 £ concordant twin pairs] þ discordant twin pairs).

Furthermore, there was very little difference in effect sizes between the pair-wise

and proband-wise estimates. Substituting the proband-wise calculations for the

pair-wise calculations increased the unweighted mean f effect size estimate

by 0.01 (from 0.13 to 0.14), the weighted mean f effect size estimate by 0.01

(from 0.12 to 0.13), and elevated the 95% confidence interval from 0.10–0.13 to

0.12– 0.15. Odds ratios were also calculated for all proband-wise twin com-

parisons, the outcome of which yielded an unweighted mean effect size of 2.15, a

weighted mean effect size of 1.92, and a 95% confidence interval of 1.33–2.61.These findings imply that neither the proband-wise method of calculating twin

concordance nor the odds ratio approach advocated by Fleiss[37] significantly

alter the pattern of results obtained from phi coefficients of pair-wise twin data.

The outcomes achieved when behavior genetic research on alcohol abuse

and dependence is subjected to meta-analysis show that these patterns are

heritable to some extent, with the degree and type of influence still requiring

further clarification. At this point in time the effect of genes on alcohol misuse

cannot be denied, but neither can the effect of the environment. There has been

a discernable shift within the alcohol abuse field over the past several years which

has seen biological factors displace environmental and learning factors in

explanations of problem drinking, a shift that threatens to accelerate as genetic

mapping becomes a reality.[51,52] Whether shared environmental experience is as

pivotal to alcohol misuse as it is to crime remains to be seen, although the inter-active nature of nonshared environmental influence apparently plays a crucial

role in the initiation and maintenance of alcohol misuse. In closing it is important

to reiterate that the intent of this paper has not been to disparage or discourage

genetic research on alcohol abuse and dependence, but rather to call for greater

balance in our views on the subject. Rapprochement between the biological and

learning camps is within our grasp but only if we are willing to reject genetic

and environmental reductionism as a means of achieving a more comprehensive

and interactive perspective on problem drinking.

ACKNOWLEDGMENTS

The author would like to thank Scott Stoltenberg and Kerry Jang for their

assistance in providing additional data from the Curran et al. and Jang et al. [53,54]

studies, respectively. The assertions and opinions contained herein are the




private views of the author and should not be construed as official or as

reflecting the views of the Federal Bureau of Prisons or the United States

Department of Justice.

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