Posttraumatic stress disorder and its cross-generational familial relationship with drug use disorder and alcohol use disorder: an extended Swedish adoption study

ABSTRACT

Objective: Information on how parental risk for posttraumatic stress disorder (PTSD) relates to their children’s risk for drug use disorder (DUD) and alcohol use disorder (AUD) is limited. This study is the first to utilize an extended adoption design which can address questions about the degree of, and sources of, cross-generational and cross-disorder transmission of PTSD and substance use disorders.

Method: We examined diagnoses using Swedish National registries for parents and their adult offspring (n = 2,194,171, born 1960–1992) from six types of families (intact (1), not lived with biological father (2) or mother (3), step father (4), step mother (5), and adoptive (6)). Parent–child resemblance was assessed by tetrachoric correlation.

Results: PTSD and DUD showed an approximately symmetrical cross-generational cross-disorder relationship. Conversely, AUD in parents was more related to the risk for PTSD in offspring compared to the reverse direction. The cross-disorder cross-generation transmission correlations for PTSD to DUD were higher than those for PTSD to AUD. Genetic and rearing correlations for PTSD-DUD were estimated at + .79 (CI: .66, .91) and + .49 (CI: .33, .65), significantly higher than those for PTSD-AUD + .59 (CI: .48, .71) and + .28 (CI: .12, .44).

Conclusions: PTSD and the substance use disorders demonstrated cross-transmission, but more so for DUD. PTSD and DUD demonstrated highly correlated genetic effects, and moderately correlated rearing effects. Correlations of genetic and rearing effects between PTSD and AUD were lower than those for PTSD and DUD.

HIGHLIGHTS

• We sought to examine how parental risk for posttraumatic stress disorder (PTSD) relates to offspring risk for drug use disorder (DUD) and alcohol use disorder (AUD), and vice versa, via an extended adoption design which can address questions about the degree of, and sources of, cross-generational and cross-disorder transmission.

• We used a population register-based design and found that the cross-disorder cross-generation transmission genetic and rearing correlations for PTSD to DUD were higher than those for PTSD to AUD.

• Our findings suggest that cross-disorder intergenerational transmission between PTSD and the substance use disorders, but to a higher degree for PTSD-DUD compared to PTSD-AUD.

1. Introduction

Posttraumatic stress disorder (PTSD) and substance use disorders, such as drug and alcohol use disorders (AUD; DUD, respectively), commonly co-occur (Blanco et al., 2013) with the lifetime prevalence of any substance use disorder being twice as high for individuals with PTSD vs. those without (Shorter et al., 2015). Common genetic influences may partially explain comorbidity between PTSD and these disorders. Indeed, PTSD and substance use disorders also have overlapping genetic risk with both twin studies and molecular studies evidencing a significant and moderate etiologic overlap between PTSD and both alcohol dependence and drug dependence (Sheerin et al., 2020; H. Xian et al., 2000).

In addition to a common factors hypothesis, such as shared genetic risk, the two most common hypotheses postulated to explain this co-occurrence are the self-medication hypothesis and the susceptibility hypothesis. The self-medication hypothesis is a causal model that suggests that those with PTSD are more likely to develop a substance use disorder due to a tendency to use said substance to cope with negative internal experiences (Khantzian, 1997). In contrast, the susceptibility model posits that substance use may increase susceptibility to developing PTSD through environmental (e.g. increased trauma exposure) or physiological (e.g. altered physiological reactivity to stress) pathways (Danovitch, 2016). To date, these hypotheses have largely only been conceptualized and studied in a within-person context.

There is evidence to suggest that there are cross-generational and cross-disorder influences on PTSD and substance use outcomes from a phenotypic standpoint. Much of the existing work in this area has focused on the cross-generational transmission of parental substance use disorder to offspring PTSD, supporting the susceptibility hypothesis (Bender et al., 2020; 2021; Hanson et al., 2006). Cross-generational transmission of a parental substance use disorder to offspring PTSD may occur through an increased risk for offspring trauma exposure due to parental substance use. Indeed, extant research has demonstrated that adolescents who report parental alcohol or drug use concurrently report higher rates of sexual assault, physical assault, or having witnessed violence than those who do not report parental alcohol or drug use (Bender et al., 2020; Hanson et al., 2006). Additional research has demonstrated that parental AUD is associated with the development of PTSD, separate from increased exposure to traumatic events (Bender et al., 2021). Less work has examined the cross-generational transmission of parental PTSD to offspring substance use (i.e. self-medication). However, there is a plethora of existing literature that evidences parental PTSD symptoms as related to negative (e.g. hostile, aggressive, neglectful, etc.) parenting behaviours (for a review see, (Leen-Feldner et al., 2013; Stover et al., 2012; van Ee et al., 2016)) which may serve as a risk factor for substance use in offspring either through their need to cope with such parenting practices or via a lack of parental oversight.

Taken together, evidence suggests that familial factors, in addition to shared genes, are important for understanding the cross-generational cross-disorder relationship between PTSD and AUD/DUD. However, the extant literature is largely reliant on intact families who share both genes and environment, thereby limiting the ability to parse out the influence of genetic vs. environmental influences. The influence of genetic and environmental influences can be separated using an adoption design where information on PTSD and substance use disorders is available for multiple generations, allowing for the determination of the degree of, and sources of, cross-generational cross-disorder transmission. However, to the best of our knowledge, there is no existing literature examining cross-generational, cross-disorder transmission of PTSD and substance use disorders.

The standard adoption design has been advanced to allow for the inclusion of family members outside of adoption. The extended adoption design includes biological parents who have not lived with their offspring and stepparents who raise children but are genetically unrelated. This methodological innovation has two major strengths: first, the design allows for increased statistical power, and second, the extended adoption study design allows for the replication of findings across different familial groups within the same study. While the extended adoption design has been applied to the cross-generational transmission of PTSD (Amstadter et al., 2024) finding evidence of substantial rearing and genetic transmission, it has yet to be applied to cross-generational and cross-disorder transmission of PTSD and substance use disorders.

In contrast, there have been several extended adoption studies examining the cross-transmission of drug and alcohol use disorder (DUD; AUD, respectively) with other disorders (Kendler et al., 2012; Kendler et al., 2023; Kendler, Ji, et al., 2015). Given that PTSD is often co-morbid with substance use disorders (Blanco et al., 2013), including DUD and AUD, and that these disorders have overlapping genetic risk (Sheerin et al., 2020; Xian et al., 2000), an extended adoption design can be used to determine the degree to which offspring rates of DUD and AUD are influenced by genes and rearing effects of parents with PTSD. Conversely, it has been demonstrated that offspring with parents with DUD/AUD have an increased risk of PTSD (Bender et al., 2020), but this study did not examine if this was due to genetic or rearing effects.

As such, the primary aim of the present paper is to clarify the nature of the cross-generational genetic and familial environmental risk factors for PTSD and cross-transmission with AUD/DUD via four primary research questions using a nationwide Swedish sample: 1. Are there cross-generational relationships between PTSD → DUD (consistent with a cross-generational self-medication hypothesis), and between DUD → PTSD (consistent with a cross-generational susceptibility hypothesis), and if so, are these due to genetic or rearing effects? 2. Are there cross-generational relationships between PTSD → AUD (consistent with a cross-generational self-medication hypothesis), and between AUD → PTSD (consistent with a cross-generational susceptibility hypothesis), and if so, are these due to genetic or rearing effects? 3. Are the cross-generational effects for PTSD and the substance use disorders (i.e. DUD, AUD) of similar magnitude? 4. Are the cross-generational genetic and rearing effects for PTSD and substance use disorders (i.e. DUD and AUD) correlated? Answering these questions will provide critical information about the etiology of PTSD and highly comorbid substance use disorders.

2. Methods

Information for this study was collected from nationwide Swedish registers (see Supplemental Methods Table 1). Each person’s unique identification number, having been replaced with serial numbers for confidentiality, were used for registry linkages. Using the Swedish Hospital Discharge Register, Outpatient Care Register and nationwide primary care data, PTSD was defined by using ICD-9 code 308 and ICD-10 codes F43.1, F43.0 and F62.0. In addition to the already mentioned registers/sources of data, cases of DUD and AUD were identified in the Prescribed Drug Register, Cause of Death Register, Criminal Register and Suspicion Register (see Supplemental Methods Table 2 for details).

Table 1.

Sample size, birth year, age and sex distributions across the six family types included in the study.

	Intact Families	NLW Father Families	NLW Mother Families	Stepfather Families	Stepmother Families	Adoptive Families
Sample size offspring	2,000,648	106,032	5,824	93,432	17,007	12,392
Sample size biological mother	2,000,648	77,541	5,824	68,777	NA	12,240
Sample size biological father	2,000,648	106,032	964	NA	4,385	7,747
Offspring
Year of birth, mean (sd)	1975.7 (9.5)	1974.3 (9.6)	1968.7 (8.0)	1973.8 (8.4)	1972.6 (8.6)	1964.6 (7.7)
Age, mean (sd)	41.3 (9.9)	42.5 (10.1)	47.7 (9.3)	43.0 (9.2)	43.9 (9.5)	51.9 (9.1)
Male, No. %	1,048,285 (52.4)	53,852 (50.8)	3,141 (53.9)	46,735 (50.0)	9,220 (54.2)	6,567 (53.0)
Female, No. %	952,363 (47.6)	52,180 (49.2)	2,683 (46.1)	46,697 (50.0)	7,787 (45.8)	5,825 (47.0)
Average biological parental level of educationa
Pre-secondary education, No. %	284,336 (14.2)	13,131 (12.4)	1,633 (28.0)	13,520 (14.5)	4,343 (25.5)	4,654 (37.6)
Secondary education, No. %	988,299 (49.4)	59,903 (56.5)	2,965 (50.9)	54,063 (57.9)	8,192 (48.2)	5,788 (46.7)
Post-secondary education, No. %	727,748 (36.4)	32,960 (31.1)	1,188 (20.4)	25,643 (27.4)	3,904 (23.0)	1,854 (15.0)
Average lived with parental level of educationa
Pre-secondary education, No. %	284,336 (14.2)	26,431 (24.9)	2,235 (38.4)	31,797 (19.1)	5,216 (30.7)	3,377 (27.3)
Secondary education, No. %	988,299 (49.4)	52,150 (49.2)	2,071 (35.6)	41,351 (54.3)	7,393 (43.5)	5,578 (45.0)
Post-secondary education, No. %	727,748 (36.4)	27,191 (25.6)	1,084 (18.6)	20,152 (26.6)	4,358 (25.6)	3,406 (27.5)
No of siblings to offspring, median (IQR)b
Full siblingc	1 (1-2)	0 (0-0)	0 (0-1)	0 (0-1)	1 (0-1)	0 (0-1)
Maternal half siblingc	0 (0-0)	1 (0-2)	1 (0-2)	1 (1-2)	NA	2 (1-3)
Paternal half siblingc	0 (0-0)	2 (0-3)	0 (0-2)	NA	1 (0-2)	0 (0-2)
Non-biological step/adoptive sibling	NA	NA	NA	1 (0-1)	1 (1-2)	0 (0-1)

^aWhen the average level fell between two categories, a rounding off to the higher educational level was performed. ^bIncluding siblings detected in the Swedish registries.

^cBiological sibling.

Note: NLW: not lived with; sd: standard deviation; IQR: interquartile range.

Table 2.

Prevalence of PTSD, AUD, and DUD in the Relatives from the Six Family Types Included in this Study.

	Disorder	Intact Families	NLW Father Families	NLW Mother Families	Stepfather Families	Stepmother Families	Adoptive Families
All offspring	PTSD AUD DUD	5.3 3.7 3.2	9.7 10.1 11.1	9.7 13.1 9.5	9.3 9.6 8.9	10.8 13.8 12.6	8.7 12.9 7.7
Female offspring	PTSD AUD DUD	7.7 2.2 2.0	13.4 6.6 7.4	13.6 8.3 8.0	12.5 5.9 5.9	14.5 9.6 9.9	12.1 8.3 6.4
Male offspring	PTSD AUD DUD	3.2 5.0 4.4	6.2 14.7 13.5	6.3 17.2 10.7	6.0 13.2 11.8	7.6 17.2 14.9	5.6 17.1 8.8
Biological mothers	PTSD AUD DUD	3.4 2.2 1.1	7.0 7.7 4.6	4.0 18.1 9.2	6.0 5.8 2.9	NA	2.8 15.2 6.5
Biological fathers	PTSD AUD DUD	1.3 6.2 0.9	2.7 28.7 9.1	1.1 13.3 2.5	NA	1.8 10.6 1.5	1.2 31.7 6.8
Stepmother or adoptive mother	PTSD AUD DUD	NA	NA	NA	NA	3.5 3.7 1.7	1.5 2.2 1.2
Stepfather or adoptive father	PTSD AUD DUD	NA	NA	NA	2.0 12.0 2.1	NA	0.5 3.7 0.6

PTSD: post-traumatic stress disorder; DUD: drug use disorder; AUD: alcohol use disorder.

The study population (n = 3,856,464) included all individuals born in Sweden between 1960-1992, who were alive and resided in Sweden at least until the age of 20 and the year 1987, capturing the period of highest risk for onset of the disorders. Study end was set at 31 December 2018. In the registers, we searched for the number of years, during ages 0–15, that the individuals, here called offspring, resided in the same household and geographic area as their biological mother, biological father, and possible stepfather, stepmother, adoptive mother and adoptive father. From 1960 to 1985 (every fifth year), we used household identification numbers from the Population and Housing Census to define family types.

We defined the following types of families: (i) intact families that included offspring residing from ages 0 to 15 years in the same household with both the biological mother and father; (ii) families with NLW (not-lived-with) father/mother, that included offspring who never resided in the same household or Statistical Area Market Survey (SAMS) area as the biological father/mother; (iii) two types of stepfamilies (stepfather/stepmother) that included offspring who did not reside the entire period between ages 0 and 15 with the biological father/mother and resided at least 10 of these years with a biologically unrelated man/woman 18–50 years older; (iv) adoptive families that included offspring adopted at younger than 5 years, with information available on both adoptive parents and at least one biological parent. The adoptive parents had to be biologically unrelated to the offspring and the offspring had to reside with each adoptive parent for at least 10 years between the ages 0 and 15. As domestic adoptions declined substantially in Sweden in recent decades, we expanded modestly our adoption cohort to maximize sample size, including offspring born from 1955 to 1992. The NLW- and step-parents were defined so that their relationships with their offspring resembled those seen between an adoptee and his/her biological and adoptive parents. Further, to be recorded as a biological mother in the NLW father or stepfather families or a biological father in the NLW mother or stepmother families, where the aim was for the biological mother/father to reflect a genes + rearing relationship with her/his offspring, the offspring had to reside from the age of 0 to 15 with the biological mother/father. Of the complete offspring source population, a selected sample of 57% (n = 2,194,171) was possible to classify into one of our family types at study. Individuals could not be partly classified into a family type (e.g. if the biological parents lived together until age 14 of offspring, that offspring was excluded from analyses). The definition of family is made once per offspring (not per family), thus, it is possible that siblings could be classified into different family types, or that one sibling is included and one excluded in analyses. Most offspring having separated biological parents will be excluded from the study, unless one parent immediately left/were never present and/or a step-parent lived with the offspring for a longer period of time.

For all family types, parents had to be alive throughout 1986 and had to reside in Sweden during some period of time from 1987 and onwards. As a proxy for the socioeconomic status of the offspring, we collected educational level for both biological and lived-with parents from the total population register and Longitudinal integrated database for health insurance and labour market studies (LISA). There exist overlaps in the parent-offspring relationships between the NLW families and the stepfamilies. When doing joint statistical analyses across family types, parent-offspring relationships included in, for example, a stepfather family was removed from the NLW father family group, so that each relationship was only calculated once.

In our parent-offspring pairs, we calculated tetrachoric correlations – which represent the correlation in relatives for a latent underlying normally distributed liability to illness (Ekström, 2011) – for PTSD transmission, DUD transmission, AUD transmission, PTSD to DUD cross-transmission, PTSD to AUD cross-transmission, DUD to PTSD cross-transmission and AUD to PTSD cross-transmission. We used this measure because of its ease of interpretability (Falconer, 1989) and its insensitivity to changes in base rates (Babchishin & Helmus, 2016), given the differing rates of PTSD, AUD and DUD across our family types. To calculate weighted tetrachoric correlations and for testing for heterogeneity across families, we use a meta-analysis fixed effects model (Borenstein et al., 2010). The model is fixed as samples of data come from the same population. For the heterogeneity tests, a significance level of 0.05 was utilized. Bonferroni correction was applied when performing multiple testing.

We also calculated the genetic correlation and the rearing correlation between the diagnosis combinations PTSD and DUD, and PTSD and AUD. We calculated the genetic correlation, $r_g$, and the rearing correlation, $r_r$, between PTSD and DUD, as well as between PTSD and AUD, using this formula (for simplicity DUD has been used, but can be switched to AUD):

$$r={\displaystyle \frac{\mathrm{Cov}(\mathrm{PTSD},\mathrm{DUD})}{\sqrt{V(\mathrm{PTSD}),V(\mathrm{DUD})}}={\displaystyle \frac{r(\mathrm{PTSD},\mathrm{DUD})}{\sqrt{r(\mathrm{PTSD},\mathrm{PTSD}),r(\mathrm{DUD},\mathrm{DUD})}}.}}$$

For the correlation, $r(\mathrm{PTSD},\mathrm{DUD})$ we made use of a weighted tetrachoric correlation explaining parent-offspring cross-transmissions from PTSD to DUD as well as from DUD to PTSD. For the correlations $r(\mathrm{PTSD},\mathrm{PTSD})$ and $r(\mathrm{DUD},\mathrm{DUD})$ we used the weighted tetrachoric correlations explaining parent-offspring transmissions from PTSD to PTSD and DUD to DUD, respectively. For the genetic correlation, we made use of 131,843 parent-offspring pairs (based on 121,794 offspring) reflecting a genes-only relationship. These pairs were found in the following families: NLW father (biological father), NLW mother (biological mother) and adoptive (biological fathers and biological mothers). For the rearing correlation, we made use of 135 223 parent-offspring pairs (based on 116 797 offspring) reflecting a rearing only relationship. These pairs were found in the following families: stepfather (stepfather), stepmother (stepmother) and adoptive (adoptive fathers and adoptive mothers). For the 95% confidence intervals, we used quantiles from the normal distribution along with estimated standard errors based on jackknife resampling methods, i.e. calculating the above formula n times (n = 121,794 for the genetic correlation and n = 116,797 for the rearing correlation). For each calculation, offspring was removed from the sample, one at a time.

Data analysis was conducted from 3 March 2023 to 21 March 2023 (see Supplemental Methods Table 3 for details). Statistical analyses were performed using R, version 4.2.1 version 4.2.1 (Team, 2022) and SAS, version 9.4 (Inc., 2016).

Table 3.

Tests of transmission of PTSD, DUD, and AUD, and cross-disorder transmission, from mothers and fathers using weighted estimates across all family types.

	Mothers		Fathers		Weighted estimate		Nominal P value for test of heterogeneity a
Cross-Generational Transmission
PTSD→PTSD	Estimate	95% CI	Estimate	95% CI	Estimate	95% CI
Genes + rearing	0.16	0.15,0.17	0.14	0.13,0.15	0.15	0.15,0.16	<.001*
Genes only	0.06	0.00,0.12	0.09	0.06,0.11	0.08	0.06,0.11	0.51
Rearing only	0.11	0.06,0.15	0.10	0.07,0.13	0.10	0.07,0.12	0.58
DUD→DUD
Genes + rearing	0.20	0.19,0.21	0.21	0.20,0.22	0.21	0.20,0.21	<.001*
Genes only	0.24	0.19,0.28	0.28	0.27,0.30	0.28	0.26,0.29	0.07
Rearing only	0.10	0.05,0.16	0.14	0.11,0.17	0.14	0.11,0.16	0.33
AUD→AUD
Genes + rearing	0.19	0.19,0.20	0.19	0.19,0.20	0.19	0.19,0.20	<.001*
Genes only	0.19	0.16,0.23	0.20	0.18,0.21	0.20	0.18,0.21	0.85
Rearing only	0.07	0.03,0.11	0.08	0.06,0.09	0.08	0.06,0.09	0.95
Cross-Transmission of PTSD and DUD
PTSD→DUD
Genes + rearing	0.16	0.15,0.16	0.14	0.13,0.15	0.15	0.15,0.16	<.001*
Genes only	0.12	0.06,0.18	0.12	0.10,0.14	0.12	0.10,0.14	0.98
Rearing only	0.08	0.03,0.12	0.06	0.03,0.09	0.06	0.04,0.09	0.26
DUD→PTSD
Genes + rearing	0.11	0.10,0.12	0.10	0.09,0.11	0.10	0.10,0.11	<.001*
Genes only	0.11	0.06,0.16	0.12	0.10,0.14	0.12	0.10,0.13	0.79
Rearing only	0.04	−0.02,0.10	0.05	0.02,0.08	0.05	0.02,0.07	0.92
Cross-Transmission of PTSD and AUD
PTSD→AUD
Genes + rearing	0.07	0.07,0.08	0.07	0.06,0.08	0.07	0.07,0.08	0.006
Genes only	0.03	−0.03,0.09	0.01	−0.01,0.04	0.02	−0.01,0.04	0.54
Rearing only	0.00	−0.05,0.05	0.02	−0.01,0.05	0.01	−0.01,0.04	0.81
AUD→PTSD
Genes + rearing	0.09	0.09,0.10	0.08	0.08,0.09	0.09	0.08,0.09	<.001*
Genes only	0.14	0.10,0.18	0.09	0.07,0.10	0.09	0.08,0.10	0.006
Rearing only	0.04	−0.00,0.09	0.03	0.01,0.05	0.03	0.01,0.05	0.37

a) Significance threshold after Bonferroni correction for 21 tests was P < 0.05/21 = 0.002. Significant tests are marked with *. PTSD – Post-traumatic stress disorder, DUD – Drug Use Disorder, AUD – Alcohol Use Disorder.

3. Results

Descriptives. The sample sizes by type of parents and offspring, born between 1960 and 1992 (1955–1992 in adoptive families) are shown in Table 1. The average age of the offspring was 41.5 years (SD: 10.0). Sample sizes ranged across the six types of families, with the smallest being NLW mother families, and the largest being intact families. Table 2 presents the prevalence of PTSD, DUD, and AUD in parents and offspring. Notably, the prevalence of all disorders in offspring was seemingly lowest in intact families compared to other types of families, highest in disrupted families (NLW and stepparent families) and moderate in adoptive families. The prevalence of all disorders was lowest among adoptive parents, which is expected, as these parents are screened prior to approval for adoption. Additionally, expected patterns of sex differences were found among offspring and parents such that the prevalence of PTSD among females was greater than that among males across all family types. Further, the prevalence of both DUD and AUD was generally higher in males than females for offspring and parents across all family types.

3.1. Cross-generational transmission of PTSD, DUD, and AUD

The weighted estimates (tetrachoric correlations and 95% CIs) of within-disorder cross-generational transmission are presented in Table 3. Detailed results in the Swedish registries for DUD and AUD have been published before (Kendler et al., 2012; Kendler et al., 2023; Kendler, Ji, et al., 2015) and are under review for PTSD (Amstadter et al., 2024). The descriptions of correlations across all family types are presented in the Supplemental Results and in Supplementary Results Table 1. For PTSD the weighted estimates (tetrachoric correlations, 95% CIs) from parents reflecting genes plus rearing was .15 (.15, .16), reflecting genes only was .08 (.06 .11), and reflecting rearing only was .10 (.07, .12). The weighted estimates of transmission of DUD across generation from mothers and fathers was .21 (.20, .21), .28 (.26, .29), and .14 (.11, .16), for genes plus rearing, genes only, and rearing only, respectively. The cross-generational transmission of AUD, reflected by the weighted tetrachoric correlations, are .19 (.19, .20), .20 (.18, .21), and .08 (.06, .09), for genes plus rearing, genes only, and rearing only, respectively.

3.2. Cross-Transmission of PTSD and DUD

Cross-Transmission of PTSD to DUD. To examine our primary research question, what are the sources of the cross-generational relationship between PTSD and DUD, tetrachoric correlations for parent-offspring PTSD to DUD transmission were calculated and are shown in the second section of Supplementary Results Table 1. Table 3 and Figure 1 present the weighted estimates of transmission of PTSD to DUD from mothers and fathers. Significant heterogeneity was found for genes plus rearing, likely driven by the substantially higher sample size for intact families and thus power to detect very small effects. The weighted estimates (and 95% CIs) for genes plus rearing, genes only, and rearing only were .15 (.15, .16), .12 (.10, .14), and .06 (.04, .09).

Figure 1.

Summary results of the sources of cross-generational cross-disorder transmission of PTSD and DUD. Figure 1 shows the weighted tetrachoric correlations (± 95% CIs) on the Y-axis reflecting parent-offspring relationships due to (1) genes plus rearing, (2) genes only, and (3) rearing only for cross-generational transmission of PTSD to PTSD, PTSD to DUD, DUD to PTSD, and DUD to DUD.

Cross-Transmission of DUD to PTSD. Tetrachoric correlations representing parent-offspring transmission of DUD to PTSD were computed (see second section of Supplementary Table 1). Table 3 and Figure 1 present the weighted estimates reflecting transmission of DUD to PTSD from mothers and fathers, for genes plus rearing (.10 [.10, .11]), genes only (.12 [.10, .13]), and rearing only (.05 [.02, .07]). Significant heterogeneity was found for genes plus rearing.

3.3. Cross-Transmission of PTSD and AUD

Cross-Transmission of PTSD to AUD. To answer the next part of our primary research question, parent-offspring correlations were computed for transmission of PTSD to AUD. The bottom section of Supplementary Table 1 presents the tetrachoric correlations for parent-offspring transmission of PTSD to AUD. Table 3 and Figure 2 show the weighted estimates reflecting transmission of PTSD to AUD from mothers and fathers, for genes plus rearing (.07 [.07, .08]), genes only (.02 [−.01, .04]), and rearing only (.01 [−.01, .04]).

Figure 2.

Summary results of the sources of cross-generational cross-disorder transmission of PTSD and AUD. Figure 2 shows the weighted tetrachoric correlations (±95% CIs) on the Y-axis reflecting parent-offspring relationships due to (1) genes plus rearing, (2) genes only, and (3) rearing only for cross-generational transmission of PTSD to PTSD, PTSD to AUD, AUD to PTSD, and AUD to AUD.

Cross-Transmission of AUD to PTSD. The tetrachoric correlations representing parent-offspring transmission of AUD to PTSD are shown in the lower section of Supplementary Table 1. The weighted correlations are presented in Table 3 and in Figure 2 which reflect transmission of AUD to PTSD from mothers and fathers for genes plus rearing (.09 [.08, .09]), genes only (.09 [.08, .10]), and rearing only (.03 [.01, .05]). Significant heterogeneity was found for genes plus rearing.

Genetic and Rearing Correlation of PTSD and DUD, and PTSD and AUD. From the genes only and rearing only results we could calculate the genetic and rearing cross-generational correlations between PTSD and DUD, and for PTSD and AUD. For PTSD and DUD the genetic correlation was .79 (.66, .91), and for PTSD and AUD the genetic correlation was .59 (.48, .71). The difference between these two genetic correlations (.19 [.09-.29]) was significant (p = .0001). The rearing correlation for PTSD and DUD was .49 (.33, .65), and for PTSD and AUD it was .28 (.12, .44). This difference, .21 (.01, .40), was modestly significant (p = .0385).

4. Discussion

Using the Swedish national registries, we aimed to examine the cross-generational cross-disorder transmission between PTSD and substance use disorders. This study represents the first extended adoption design to examine the cross-generational and cross-disorder relationship between PTSD and substance use disorders. We sought to answer four primary questions, each to be discussed in turn.

We first sought to determine the nature and sources of cross-generational relationships between parental PTSD and offspring DUD and vice versa; notably, our results of within-disorder transmission for PTSD to PTSD are discussed in (Amstadter et al., 2024). Our results suggest a moderate relationship of cross-generational influence from PTSD to offspring DUD. The weighted tetrachoric estimate (95% CI) within intact families was + .15 (.15, .16). The estimate for genes only and rearing only was + .12 (.10, .14) and + .06 (.04, .09), respectively. This pattern of findings is roughly consistent with an additive relationship (i.e. genes only plus rearing only estimates are close to that yielded from intact families). These results suggest that the genes and rearing influences that cause risk for PTSD also predispose to offspring DUD, with approximately 67% of the transmission resulting from genetic influences and approximately 33% stemming from rearing transmission. These results are consistent with the common factors hypothesis, and with prior evidence of shared genetic risk between PTSD and substance use disorders (Sheerin et al., 2020; Xian et al., 2000). Notably, in contrast to the within-disorder effects for PTSD (Amstadter et al., 2024) wherein the rearing effects were higher than the genetic effects, the reverse is true in the cross-disorder context. This suggests that the rearing effects of having a parent with PTSD are more pre-disposing to PTSD than it is to DUD. However, the rearing effects in the cross-disorder context were non-trivial. The self-medication model has been extensively studied within person, positing that individuals use substances to cope with PTSD symptoms (for review see (Hawn et al., 2020)). Conceptualized in the cross-generation context, it is possible that parental modelling of avoidance behaviours, a common symptom of PTSD, contributes to offspring avoidance and thus substance use (Leen-Feldner et al., 2013). Parental PTSD has been associated with negative (e.g. hostile, aggressive, neglectful, etc.) parenting behaviours (for a review see, (Leen-Feldner et al., 2013; van Ee et al., 2016; Stover et al., 2012)) which may also be related to risk of substance use in their offspring.

Results from the model examining the effects of parental DUD on offspring PTSD also suggest a moderate impact of cross-generational influence. The genes only (+.12 [.10, .13]) and rearing only (+.05 [.02, .07]) effects were qualitatively symmetrical with the reverse direction, however, the genes plus rearing correlation was smaller for parental PTSD to DUD in offspring compared to the reverse (+.10 [.10, .11]). Similar to the reverse direction, parental DUD’s effects on offspring PTSD were largely due to genetic transmission (∼71%) with a lower, but non-trivial effect of rearing transmission (∼29%). However, in contrast to the PTSD → DUD results suggesting an additive effect, the DUD → PTSD results are more consistent with a negative interaction. Our results are consistent with findings that offspring with parents with DUD/AUD have an increased risk of PTSD (Bender et al., 2020), and our findings suggest this risk is due to both genetic and rearing effects. Prior studies have also supported cross-generational risk of PTSD in parents with and SUD (Bender et al., 2020; 2021; Hanson et al., 2006), perhaps via higher likelihood of trauma exposure among offspring of parents with SUD (Bender et al., 2020; Hanson et al., 2006).

To determine if PTSD and AUD have symmetrical cross-disorder relationships, we next examined the effect of parental PTSD on offspring AUD, and vice versa. Parental PTSD had quite modest cross-transmission to offspring AUD. Only the estimate and 95% confidence interval of genes plus rearing (.07 [.07, .08]) did not include zero. The estimates for genes only (.02 [−.01, .04]) and for rearing only (.01 [−.01, .04]) both included zero. Conversely, the cross-transmission of AUD in parents to PTSD in offspring was stronger, with weighted estimates for genes plus rearing (.09 [.08, .09]), genes only (.09, [.08, .10]), and rearing only (.03 [.01, .05]). These results suggest that the genes and rearing influences that give rise to risk for AUD in parents also predispose to offspring PTSD, with approximately 75% of the transmission resulting from genetic influences and approximately 25% stemming from rearing transmission. Thus, there is a non-symmetrical cross-disorder relationship between PTSD and AUD such that parental AUD is more related to risk of offspring PTSD than the reverse. One potential explanation for the AUD->PTSD pathway in offspring may be increased risk for trauma exposure in offspring of parents with AUD, which has been found in prior studies (Bender et al., 2020; Hanson et al., 2006).

Our third question was whether the cross-generational cross-disorder effects were of similar magnitude between PTSD and the two substance use disorders we considered. Whereas PTSD and DUD have similar cross-disorder relationships, PTSD and AUD do not. Further, the results were strikingly different when comparing the impact of parental PTSD on risk of DUD versus AUD in offspring. The impact of parental PTSD on risk of offspring AUD was lower than that of DUD with non-overlapping confidence intervals for all effects, with the difference of the greatest magnitude being that of genetic only transmission. Thus, the genes from a parent that cause risk for PTSD appear to be more closely related in the child to predisposing to DUD (.12 [.10, .14]) compared to AUD (.02 [−.01, .04]). This is an interesting finding that warrants future investigation.

Our last research question was focused on the extent to which cross-generational genetic and rearing influences were correlated between PTSD and the substance use disorders. To test this question, we calculated the genetic correlation of the cross-generational genetic influences on PTSD and the substance use disorders. The cross-generational genetic correlation between PTSD and AUD was + .59 (.48, .71), and the correlation between PTSD and DUD was + .79 (.66, .91). Despite having overlapping 95% CIs, the difference in correlation between PTSD-AUD and PTSD-DUD was substantial (+.19) and highly significant. Our findings are broadly consistent with prior twin studies that have found genetic overlap in liability between PTSD and AUD and DUD, such that roughly 40% of the additive genetic variance for PTSD is overlapping with that of AUD and DUD (Xian et al., 2000), as well as twin studies suggesting that PTSD shares genetic risk with externalizing disorders (Wolf et al., 2010). Twin and family studies of AUD and DUD also show evidence of both shared and disorder-specific risk (Kendler et al., 2011). Extended adoption results from the Swedish registries have also demonstrated that the genetic risk for AUD and DUD is correlated, but not at unity (Kendler et al., 2023). Taken together the difference in the genetic correlation between PTSD and each form of substance use disorder is notable and underscores the continued need for studies examining both AUD and DUD rather than combining the disorders into a broad substance use disorder category.

Whereas prior twin studies have examined the genetic correlation between PTSD and the substance use disorders, these studies are underpowered to detect modest shared environmental effects in the presence of moderate genetic effects (Neale et al., 1994), and thus, to our knowledge, this study is the first to estimate rearing environmental correlations. We found that rearing correlations for PTSD-DUD and PTSD-AUD to be + .49 (.33, .65) and + .28 (.12, .44), respectively. Given that these correlations are known less precisely, while significantly different, we have less confidence in this difference compared to that of the genetic correlations. These rearing environmental correlations suggest that the impact of parental PTSD and DUD/AUD on offspring are moderately inter-correlated.

Limitations. Four limitations are notable. First, our reliance on registry data, while limiting retrospective recall biases, means that AUD and DUD are based on seeking medical attention or on being involved with the criminal justice system. Extensive analyses using these definitions have been conducted, and support the validity of the definitions with evidence of high concordance across methods (Kendler, Ohlsson, et al., 2015) and biometric findings of familial associations being similar to those generated from clinical interview studies (Prescott & Kendler, 1999; Tsuang et al., 1996). Our findings may generalize more for severe substance use disorder cases given the threshold for being classified with DUD or AUD via registration is high and thus, more mild or moderate cases may not have been detected. Further, there are limitations in our PTSD variable in that cases were primarily detected from nationwide health registries, which likely represents an underestimate of the disorder as many do not seek care, and/or do not report psychiatric symptoms if they do. Second, while we were sufficiently powered to examine AUD and DUD separately, we were not able to examine specific categories of substances with the broader DUD diagnosis, nor did we account for comorbidity, suggesting directions for future research. An additional limitation stems from bias that can arise from nonrandom placement of children in adoption studies. Adopted parents are highly selected (e.g. health, stable homes, high socioeconomic status); indeed, rates of all disorders are lowest in adoptive parents, as expected. However, the extended adoption design is an innovative methodological improvement, as step-parents and not lived with parents are not as highly selected, thus adding to the generalizability of the study. Lastly, our sample was restricted to native born Swedes because data on family relations are less available for immigrants, which limits generalizability.

Conclusions and Implications. This is the first extended adoption cross-generation and cross-disorder study for PTSD. The extended adoption design, which includes other familial constellations, such as biological parents who have not lived with their offspring, and stepparents who do live with offspring but do not share their genes, affords substantially more power than traditional adoption designs. Additionally, including these familial constellations provides an opportunity for within study replication of adoption findings. Indeed, our results support that not lived with parents and step-parents are suitable proxies for biologic parents and adoptive parents, respectively, in traditional adoption designs.

We showed that PTSD and DUD have roughly similar cross-disorder cross-generation effects, whereas AUD in parents is more related to PTSD in offspring compared to the reverse direction. Similarly, while the genetic correlation between PTSD and each form of substance use disorder was moderately high, the PTSD-DUD genetic correlation was significantly greater than that of the PTSD-AUD genetic correlation. The rearing correlations were more modest, as was the difference between the PTSD-DUD and PTSD-AUD rearing correlations. These findings may be useful for teasing out the causality behind the association between PTSD and substance use disorders. Given the evidence of cross-generational cross-disorder transmission between PTSD and the substance use disorders, preventative efforts for offspring whose parents are afflicted with these conditions could be impactful.

Funding Statement

This project was supported by grants R01DA030005 and R01AA023534 from the National Institutes of Health and from the Swedish Research Council (2020-01175 and 2021-06467).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

The data are not publicly available due to restrictions with regard to the nationwide Swedish registers.

Author contribution

All authors meet the four ICMJE criteria for authorship. Drs. Amstadter and Kendler conceptualized the project and research questions. Dr. Abrahamsson conducted the analyses. Drs. J. and K. Sundquist acquired the data and assisted in interpretation of study findings. Drs. Amstadter, Cusack, and Abrahamsson wrote the manuscript, and Drs. J. Sundquist, K. Sundquist, and Kendler provided substantive edits.