Materials and Methods
Participants
As described previously (McKay et al, 2013; Olvera et al, 2011), GOBS study
subjects were recruited from two studies: The San Antonio Family Heart Study
(Mahaney et al, 1995; Mitchell et al, 1996) and the San Antonio Family Gallbladder
Study (Puppala et al, 2006). Family members of individuals who participated in these
studies were also recruited. Initially (1992 – 1995), the San Antonio Family Heart Study
included 1431 Mexican-American individuals from 42 extended families. Probands were
identified from the Hispanic community in three phases. First, a census tract comprising
a low-income neighborhood of South San Antonio was selected. Although San Antonio
is 61% Hispanic, residents of these neighborhoods were of 81% Hispanic ancestry
(www.census.gov). Second, all residential addresses within these neighborhoods were
identified in the telephone directory. Third, households were approached in random
order to determine whether any resident met established proband eligibility criteria. A
proband had to be Mexican-American, 40 – 60 years old, have a spouse willing to
participate, and have at least six offspring and/or siblings older than 16 years residing in
the San Antonio area. Once a proband was enrolled, all first-, second-, and third-degree
relatives of the proband and of the proband’s spouse, who were at least 16 years old,
were invited to participate. Mexican-American spouses of these relatives were also
invited to participate. Recruitment procedures were similar in the San Antonio Family
Gallbladder Study (1998 – 2001), which included 740 individuals from 39 MexicanAmerican pedigrees (Duggirala et al, 1999; Puppala et al, 2006). However, probands in
the Gallbladder study were required to have type-2 diabetes and only unilineal relative
recruitment was conducted. As type-2 diabetes has a lifetime prevalence approaching
30% in this population, single ascertainment for such a common disease represents
effectively random sampling. The GOBS study recruited individuals from these two
cohorts, and children and grandchildren of probands who are now older than 16 years of
age were also invited to participate. Sixty-two percent of the GOBS sample is from the
San Antonio Family Heart study, 26% from the San Antonio Family Gallbladder study,
and 12% are children or grandchildren of San Antonio Family Heart study participants.
Over 80% of all individuals contacted agreed to participate in the GOBS study. Thus,
participants were pseudo-randomly selected from the community, with the constraints
that they must be of Mexican-American ancestry and part of a large family from the San
Antonio region. Stated pedigree relationships were verified using PREST (McPeek and
Sun, 2000) on available autosomal markers.
872 Mexican-American individuals from the GOBS study are included in the
current analyses. Participants were 64% female, ranging in age from 18 – 85 years old
(43.66 years, SD 14.9). Exclusion criteria for the study were history of neurological
disorders and MRI contraindications. Reported pedigree relationships were confirmed
with autosomal markers. All participants provided written informed consent, approved by
the Institutional Review Boards at the University of Texas Health Science Center San
Antonio and Yale University.
Results
Co-morbidities. As can be seen in Table 1, individuals with a lifetime history of AUD
were more likely to have had lifetime nicotine dependence (χ2=90.16, df=1, p=2.19x10), a history of substance use disorders (χ2=92.64, df=1, p=6.26x10-22), or a mood
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disorder (χ2=27.64, df=1, p=1.46x10-7) compared to individuals without AUD raising the
possibility that these traits could confound the results presented above. Similarly, the
maximum number of alcoholic beverages consumed in a 24-hour period was
significantly higher for individuals with a lifetime AUD compared to those without
(χ2=257.78, df=1, p=5.2x10-58). However, none of these traits significantly influenced
amygdala volume: lifetime nicotine dependence (p=0.268); lifetime substance use
disorder (p=0.899); lifetime mood disorders (p=0.855); or maximum drinks in a 24-hour
period (p=0.199). Similarly, lifetime nicotine dependence (p=0.266) and history of lifetime
mood disorders (p=0.953) were not statistically associated with inferior lateral ventricle
size. Yet, history of a lifetime substance use disorder (χ2=7.81, df=1, p=0.005) and the
maximum drinks in a 24-hour period (χ2=4.64, df=1, p=0.031) were associated with
larger inferior lateral ventricles.
As previously demonstrated in this cohort (Kos et al, 2014; Olvera et al, 2011), lifetime
nicotine dependence (h2=0.742, p=3.6x10-9), lifetime substance use disorder (h2=0.914,
p=2.8x10-7), lifetime mood disorders (h2=0.493, p=1.1x10-4) and maximum drinks in a
24-hour period (h2=0.303, p=8.0x10-7) were heritable. Furthermore, these variables were
genetically correlated with risk for AUD (nicotine dependence ρg=0.656, p=0.002; lifetime
substance use disorder ρg=0.705, p=0.005; lifetime mood disorders ρg=0.818, p=0.001;
and max drinks ρg=0.900, p=4.8x10-5), suggesting that common genes influence risk for
AUD and smoking, substance misuse, and mood disorders. Despite the lack of a
phenotypic effect, and given that shared genetic factors appear to influence these traits,
including these measures as covariates could inadvertently minimize the effects of
common risk genes, biasing results.
References
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