Separation Anxiety Disorder and Adult Onset Panic Attacks Share a Common Genetic Diathesis

Separation Anxiety Disorder and Adult Onset Panic Attacks Share a Common Genetic Diathesis Roxann Roberson-Nay, PhD Virginia Commonwealth University Department of Psychiatry

The SAD PD link Don Klein proposed that childhood separation anxiety disorder (SAD) was a precursor of panic disorder (PD), a condition that generally emerges in early adulthood. During the past three decades, mixed evidence has emerged from three types of studies that either support or challenge the possibility of an etiologic link between SAD and PD: the prospective course of childhood SAD into adulthood these studies either examine retrospective report parent-child aggregation of PD-SAD.

Prospective Studies In a follow-up study of 54 children referred for treatment of SAD, 7% of individuals with a history of SAD developed PD whereas no participant in the comparison group developed PD. No other anxiety disorder was more prevalent in adults with a history of SAD relative to comparison participants, although the overwhelming majority of SAD children did not develop PD.

Prospective Studies A second longitudinal study reinterviewed children (ages 9-13) approximately 7.5 years after receiving treatment and observed: 27.8% - SAD 12.5% - Social Phobia 14.3% - Overanxious Disorder

Prospective/High-Risk Study A follow-up study of children at high and low risk for PD and major depressive disorder (MDD) ascertained through parent probands treated for PD, MDD, or control parents (total n=233) Results indicated that offspring with a history of childhood SAD were at greatest risk for developing PD and agoraphobia, with an OR of approximately 9.0 for both disorders. Odds of developing MDD were 3.2 for children with a history of SAD.

Family Studies Several family aggregation studies document greater frequency of SAD diagnoses among offspring of parents with PD, relative to offspring of healthy parents. SAD also has been linked to parental MDD with some consistency.

Limitation of Family Studies Cannot disaggregate genetic and common environment, BUT twin studies can!! With twin data, we can decompose phenotypic covariation into additive genetic (A) common (shared) environmental (C) i.e., family environment unique or non-shared environmental (E) components i.e., experiences unique to the individual (e.g., loss of a close friend)

So What do Twin Studies Tell Us about SAD and PD Twin studies suggest a heritable component to SAD, with the genetic contribution being higher for females (.46-.59) compared with males (.21-.31) and unique environmental factors being more significant for males (.69-.92) relative to females (.41-.55). For adult PD, only genetic (.47) and unique environmental factors (.57) emerge as significant influences; common (shared) environment does not appear to be an important factor.

Current Study Determine whether genetic risk factors associated with childhood SAD also relate specifically to development of panic attacks in young adulthood. We define our phenotype as panic attacks versus PD for several reasons: most all of the adult twins in our sample had not yet passed through the age of risk for PD; individuals may carry a genetic risk for a particular psychiatric syndrome that may not be expressed at a diagnostic level, but may be detectable at subthreshold levels. PD has a low lifetime prevalence rate (approximately 1.5-3.5%) thereby decreasing the amount of information available for complex twin modeling.

Types of Twins Monozygotic (MZ; identical ): result from fertilization of a single egg by a single sperm; share 100% of genetic material. Dizygotic (DZ, fraternal or nonidentical ): result from independent fertilization of two eggs by two sperm; share on average 50% of their genes.

ABD/YAFU Study Virginia Twin Study of Adolescent Behavioral Development (VTSABD) + Young Adult Follow-up (YAFU). The VTSABD was designed as an epidemiological study of twins for genetically informative analysis. 1,437 twin pairs: 27.1% monozygotic [MZ] female 16.1% dizygotic [DZ] female 20.7% MZ male 15.0% DZ male 21.0% opposite-sex DZ [OSDZ]

Quantitative vs. Qualitative Sex Effects Male and female same sex twins allows a test of quantitative sex differences, i.e., whether the magnitudes of genetic and environmental effects differ by sex for a specific phenotype. Including opposite sex twins allows a test of qualitative sex differences, which test whether different genetic and shared environmental effects are important for males and females. If different genetic influences are important for males and females, then opposite sex twins will be less genetically similar for the trait relative to DZ same-sex twins.

ABD Sample Three longitudinal waves conducted during childhood and adolescence (Child & Adolescent Psychiatric Assessment [CAPA]). The mean ages were 12.35 years (±2.59; range 8.2-18.2) at the wave one assessment 13.58 years (±2.4; range 9.3-18.3) at the wave two assessment 15.5 years (+1.6; range 12.0-18.0) at the wave three assessment About 6.45% (n=176) subjects met criteria for SAD Approximately 19.6% (n=563) met criteria for OAD

YAFU Sample These twins were contacted by phone and evaluated as young adults (i.e., age > 18) using the Structured Clinical Interview for DSM-III-R. The mean age at YAFU assessment was 21.4 years (+2.0; range 18-27). Of the twins who participated in the YAFU, approximately 265 of 2275 (11.65%) individuals met our criteria for a panic attack.

Cholesky Decomposition Twin 1 Twin2 1 or.5 1 or.5 1 1 1 1 A 1 A 2 A 1 A 2 a 11 a 21 a 22 a 11 a 21 a 22 X 1 Y 1 X 2 Y 2 X=SAD Y=AOPA X=SAD Y=AOPA

Cholesky Decomposition Twin 1 1 or.5 1 or.5 Twin2 Path estimate a 21 reflects the additive genetic contribution of phenotype 1 on phenotype 2. 1 1 A 1 A 2 a 11 a 21 a 22 1 1 A 1 A 2 a 11 a 21 a 22 X 1 Y 1 X 2 Y 2 X=SAD Y=AOPA X=SAD Y=AOPA

Multifactorial Threshold Model of Disease Single threshold Multiple thresholds unaffected affected normal mild mod severe Disease liability Disease liability

Twin modeling Examined full ACE models, which tested for quantitative and qualitative sex effects The Akaike Information Criterion (AIC) used to determine the best fitting model (lower better) The best fitting ACE model was then simplified by successively eliminating parameters (i.e., submodels: AE, CE); Cannot have an E only model. A C E

Note: Qual=qualitative sex effects; Quan=quantitative sex effects; + indicates the presence of either qualitative or quantitative sex effects or - indicates their absence from the model. The AE and CE models are nested submodels of the ACE model. * indicates the best fitting model.

Bivariate Relations: SAD and AOPA A 1 A 2.63.59.001 Childhood SAD AOPA 35%.78.11.80 SAD = Separation Anxiety Disorder AOPA = Adult Onset Panic Attacks/Disorder E 1 E 2

Bivariate Relations: SAD and AOPA A 1 A 2.63.59.001 Childhood SAD AOPA.78.11.80 E 1 E 2 1%.64% SAD = Separation Anxiety Disorder AOPA = Adult Onset Panic Attacks/Disorder

Bivariate Relations: OAD and AOPA A 1 A 2.50.04.64 Childhood OAD AOPA 0%.87.26.72 OAD = Overanxious Disorder AOPA = Adult Onset Panic Attacks/Disorder E 1 E 2

Bivariate Relations: OAD and AOPA A 1 A 2.50.04.64 Childhood OAD AOPA 0% 41%.87.26.72 OAD = Overanxious Disorder AOPA = Adult Onset Panic Attacks/Disorder E 1 E 2

Bivariate Relations: OAD and AOPA A 1 A 2.50.04.64 Childhood OAD AOPA.87.26.72 E 1 E 2 7% 52% OAD = Overanxious Disorder AOPA = Adult Onset Panic Attacks/Disorder

SAD and AOPA GAD and AOPA A 1 A 2 A 1 A 2.63.59.001.50.04.64 Childhood SAD AOPA Childhood OAD AOPA.78.11.80.87.26.72 E 1 E 2 E 1 E 2

Trivariate Cholesky Decomposition 36% 0% A1 A2 A3.59.06.49.60.03.00 Childhood SAD Childhood OAD Adult Onset Panic Attacks.81.46.74.08.32.73 E1 E2 E3

Multifactorial Threshold Model of Disease Single threshold Multiple thresholds unaffected Disease liability affected no panic panic PD attack Disease liability

Summary We found evidence of a shared genetic diathesis between childhood SAD (versus childhood OAD) and AOPA in a large general population twin sample. Our findings suggest that a genetic liability is set in motion during childhood, and this liability contributes to development of panic in the presence of environmental events experienced into adulthood.

Summary In a related manner, while OAD was not genetically associated with AOPA, this childhood syndrome did share about 10% unique environmental risk with AOPA. The trivariate Cholesky decomposition suggested moderate (21%) shared environmental risk between childhood SAD and OAD, with no significant, shared genetic pathway.

Summary A developmental psychopathology perspective that focuses on the ethologic roots of SAD and its developmental trajectory is clearly needed to guide clinical research questions. Because children with SAD, like individuals with PD, exhibit hypersensitivity to cues of impending suffocation during exposure to rising levels of CO 2, Klein s suffocation false-alarm theory may have important implications in the understanding of this childhood disorder. DIDN T HE SAT THIS

Limits of Twin Models Twin models do a good job of sorting out contributions of genes and environment. BUT do not help with identifying specific genes and environmental factors. Need other methods segregation analysis linkage and association (genes) discordant twins multivariate kinship studies (environment) translational animal models

Email: rrobersonnay@vcu.edu Acknowledgement of Co-Authors Lindon J. Eaves, Ph.D. Kenneth S. Kendler, M.D. John M. Hettema, M. Judy L. Silberg, Ph.D. K01-Mentored Research Scientist Development Award from the NIMH (Primary Mentor: Kenneth S. Kendler)