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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:118– 126 (2008) A R T I C L E The Genetic Basis of Panic and Phobic Anxiety Disorders JORDAN W. SMOLLER,* ERICA GARDNER-SCHUSTER, AND JENNIFER COVINO Panic disorder and phobic anxiety disorders are common disorders that are often chronic and disabling. Genetic epidemiologic studies have documented that these disorders are familial and moderately heritable. Linkage studies have implicated several chromosomal regions that may harbor susceptibility genes; however, candidate gene association studies have not established a role for any specific loci to date. Increasing evidence from family and genetic studies suggests that genes underlying these disorders overlap and transcend diagnostic boundaries. Heritable forms of anxious temperament, anxiety-related personality traits and neuroimaging assays of fear circuitry may represent intermediate phenotypes that predispose to panic and phobic disorders. The identification of specific susceptibility variants will likely require much larger sample sizes and the integration of insights from genetic analyses of animal models and intermediate phenotypes. ß 2008 Wiley-Liss, Inc. KEY WORDS: panic; anxiety disorders How to cite this article: Smoller JW, Gardner-Schuster E, Covino J. 2008. The genetic basis of panic and phobic anxiety disorders. Am J Med Genet Part C Semin Med Genet 148C:118–126. INTRODUCTION Although panic and phobic anxiety were described well before the 20th century, it was not until the publication of DSM-III in 1980 that the modern definitions of panic and phobic anxiety disorders formally entered psychiatric nosology. According to DSM-IV, panic disorder is defined by recurrent, unexpected panic attacks that are associated with a least Jordan W. Smoller, M.D., Sc.D. is Associate Professor of Psychiatry, Harvard Medical School, Associate Professor in the Department of Epidemiology, Harvard School of Public Health, Director, Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Boston, MA and co-Director, Genetics and Genomics Unit, Clinical Research Program, Massachusetts General Hospital, Boston, Massachusetts. Ms. Gardner-Schuster is Clinical Research Coordinator, Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Boston, Massachusetts. Ms. Covino is a Research Assistant in the Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Boston, Massachusetts. *Correspondence to: Jordan W. Smoller, M.D., Sc.D., Center for Human Genetic Research, Simches Research Building, 185 Cambridge St., Boston, MA 02114. E-mail: [email protected] DOI 10.1002/ajmg.c.30174 ß 2008 Wiley-Liss, Inc. 1 month of at least one of the following: persistent concern about having additional attacks, worry about the implications of the attack or its consequences, or a significant change in behavior as a result of the attacks. DSM-IV includes three phobic disorders. The first, agoraphobia without a history of panic disorder involves agoraphobia related to the fear of developing panic-like symptoms. Agoraphobia itself is defined by anxiety about being in places or situations from which escape might be difficult (or embarrassing) or in which help may not be available in the event of having an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobia can occur as a complication of panic disorder (panic disorder with agoraphobia) or alone (agoraphobia without a history of panic disorder). Social anxiety disorder (aka social phobia) is characterized by marked fear and avoidance of one or more social or performance situations. Affected individuals recognize that their fear is excessive and experience significant impairment as a result of their anxiety and avoidance. The symptoms of specific phobia are the same but the focus of the fear and avoidance is on a specific object (e.g., animals) or non-social situation (e.g., being in closed spaces). Panic and phobic anxiety disorders are common disorders that are responsible for a substantial burden of suffering and economic costs [Greenberg et al., 1999]. In addition, both panic and phobic anxiety have been linked to increased cardiovascular morbidity and mortality [Albert et al., 2005; Smoller et al., 2007]. Table I shows the estimated lifetime prevalence and median age of onset of these disorders. As shown, the phobic disorders are more common than panic disorder and tend to have an earlier onset. It should be noted that while panic attacks are a defining feature of panic disorder, they may occur as symptoms of phobic disorders as well, in which case they are precipitated by the feared stimulus. Panic attacks may also occur sporadically in the absence of an anxiety disorder. The lifetime prevalence of isolated panic attacks has been estimated at 22.7% [Kessler et al., 2006]. There has been controversy in the literature about the relationship between agoraphobia and panic disorder. The prevailing view in American psychiatry, as reflected in DSM-IV, has been that agoraphobia (AG) is almost always a complication of panic disorder (PD). An alternative view, more closely allied with European psychiatry and reflected in ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) [Noyes et al., 1986; Mendlewicz et al., 1993; Goldstein et al., 1994; Fyer et al., 1995, 1996; Horwath et al., 1995; Maier et al., 1995], and have documented an increased risk of PD (5–16%) among relatives of affected individuals. Furthermore, early-onset PD appears to increase the familial aggregation of PD: Goldstein et al.  found a 17-fold increased risk of PD in first-degree relatives of probands with onset by age 20 but only a 6-fold increase when the proband’s onset was after age 20. Based on a weighted summary of recurrence risks from these studies, first degree relatives of PD probands have a 7-fold increased risk of the disorder compared to relatives of unaffected controls. Family studies have also demonstrated the familial nature of phobic disorders [Noyes et al., 1986; Fyer et al., 1993, 1995; Stein et al., 1998]. As shown in Table II, first-degree relatives of probands with each of the phobic disorders have a six- to ninefold increased risk of the disorder. TABLE I. Prevalence and Age of Onset of Panic and Phobic Disorders Disorder Panic disorder (PD) Agoraphobia without PD Social anxiety disorder Specific phobia LTP (%) AAO (years) 4.7 1.4 12.1 12.5 24 20 13 7 LTP, lifetime prevalence; ‘‘AAO’’ median age of onset. Data from Kessler et al. . ICD-10, is that agoraphobia is a distinct disorder which may or may not follow the onset of panic attacks. In ICD-10, the diagnosis of panic disorder with agoraphobia is given only if a primary diagnosis of agoraphobia has been excluded. Epidemiologic studies support the notion that AG can commonly occur in the absence of panic disorder. In the National Comorbidity Survey Replication study, approximately 40% of individuals with AG never met criteria for PD [Kessler et al., 2006]. GENETIC EPIDEMIOLOGY OF PANIC AND PHOBIC ANXIETY DISORDERS Family and twin studies of panic disorder and phobic disorders have provided consistent evidence that these phenotypes are familial and heritable. As discussed below, there is also evidence that genetic influences on these disorders overlap to some degree. 119 Family Studies Family studies examine whether a phenotype aggregates in families by comparing the prevalence of the phenotype among relatives of affected probands to the prevalence among relatives of unaffected controls. Six controlled family studies that included probands with PD have been reported Six controlled family studies that included probands with PD have been reported, and have documented an increased risk of PD (5–16%) among relatives of affected individuals. Furthermore, early-onset PD appears to increase the familial aggregation of PD: Twin Studies Although family studies have clearly documented that panic and phobic disorders aggregate in families, they are unable to distinguish genetic and environmental contributions. Twin studies, by comparing concordance rates of genetically identical (MZ) versus nonidentical (DZ) twins, can estimate the TABLE II. Weighted Summary Risks From Controlled Family Studies of Panic and Phobic Disorders PD Proband diagnosis PD AWOPD SAD SP Risk to relatives (%) 10.6 6.6 7.9 0.0 AWOPD SAD SP Risk to Risk to Risk to OR (95% CI) relatives (%) OR (95% CI) relatives (%) OR (95% CI) relatives (%) OR (95% CI) 7.0 (4.4–11.3) 4.12 (2.1–7.9) 5.0 (2.5–9.7) 0 (0–4.6) 2.6 8.6 1.9 0 2.5 (1.1–5.8) 8.8 (4.2–19.6) 1.8 (0.19–8.2) 0 (0–7.5) 4.1 3.4 17.3 9.3 1.2 (0.69–2.2) 1.0 (0.43–2.2) 6.0 (3.7–9.8) 3.0 (0.87–8.0) 5.9 2.7 12.5 23.4 1.5 (0.71–1.8) .50 (0.19–1.2) 2.6 (1.6–4.2) 5.6 (2.8–10.9) PD, panic disorder; AWOPD, agorpahobia without a history of panic disorder; SAD, social anxiety disorder; SP, specific phobia. a Risk to first degree relatives of affected probands. b Odds ratio and 95% confidence interval for risk to first degree relatives of affected vs. control probands. Weighted summary data from Noyes et al. , Fyer et al. [1993, 1995, 1996], Mendlewicz et al. , Goldstein et al. , Horwath et al. , Maier et al. , and Stein et al. . Bolded values indicate significant familial aggregation of phenotypes. 120 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) proportion of the population variance in disorder risk attributable to genes (i.e., heritability). Twin studies of panic and phobic disorders have indeed demonstrated that these phenotypes are moderately heritable. A meta-analysis of high-quality twin studies by Hettema et al.  estimated heritabilities of 0.43 for PD and 0.20–0.39 for phobic disorders. In a more recent analysis of the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, comprising more than 5,000 twins, Hettema et al.  reported heritabilies of 0.28 for PD, 0.36 for agoraphobia, 0.10 for social anxiety disorder and 0.24 for specific phobias. Thus, genes contribute to these disorders, but environmental influences are substantial. Multivariate modeling of twin data suggest little contribution of common shared environment (e.g., experiences and familial factors common to both twins) with most of the variance attributable to individualspecific environment (which also includes measurement error) [Hettema et al., 2001, 2005]. Linkage Studies Having established that genetic factors influence panic and phobic disorders, several groups have undertaken linkage studies to map the relevant loci. As shown in Table III, linkage analyses of PD have implicated several chromosomal regions including 1q [Gelernter Having established that genetic factors influence panic and phobic disorders, several groups have undertaken linkage studies to map the relevant l oci. As shown in, linkage analyses of PD have implicated several chromosomal regions including 1q, 2q, 7p, 9q, 12q, 13q, 15q, and 22q. et al., 2001], 2q [Fyer et al., 2006], 7p [Knowles et al., 1998; Crowe et al., 2001], 9q [Thorgeirsson et al., 2003], 12q [Smoller et al., 2001], 13q [Weissman et al., 2000; Hamilton et al., 2003], 15q [Fyer et al., 2006], and 22q [Hamilton et al., 2003]. Of note, the strongest evidence of linkage has been found when phenotype definitions have been broadened beyond the DSM boundaries of diagnosis. Strong evidence for the 13q locus was found ARTICLE when the phenotype was defined as a syndrome that included PD as well as several other medical conditions (mitral valve prolapse, serious headaches, and/or thyroid problems) [Weissman et al., 2000; Hamilton et al., 2003]. In another study of multiplex Icelandic families, Thorgeirsson et al.  observed a genomewide significant Lod score of 4.18 on chromosome 9q for a phenotype that included comorbid anxiety disorders. In the largest linkage analysis to date, Fyer et al.  reported genomewide significant linkage to 15q using a broad panic phenotype that included sporadic and limited symptom panic attacks in addition to PD. However, as is evident in Table III there has been little consistency in linkage scans for PD and data for phobic disorders has been quite limited. Association Studies In recent years, it has become clear that linkage analysis has limited power to identify loci influencing complex (non-Mendelian) traits. Association analyses, which examine the co-occurrence of a phenotype with specific genetic variants, have become the predominant method for identifying susceptibility loci for complex traits. However, TABLE III. Results of Linkage Studies of Panic and Phobic Anxiety Disorders Crowe et al.  Gelernter et al. a Smoller et al.  Hamilton et al.  Thorgeirsson et al.  Gelernter et al. a Gelernter et al. a Fyer et al.  Kaabi et al. a a Families Region of peak evidence Phenotype 23 20 7p (Lod ¼ 2.2) 1q (Lod ¼ 2.1), 11p (Lod ¼ 2.0) 3q (NPL ¼ 2.75, P ¼ 0.005) 12q (NPL ¼ 4.96, P ¼ 0.006) 13q (HLod ¼ 3.57), 22q (HLod ¼ 4.11) 9q (Lod ¼ 4.18) 14q (Lod ¼ 3.70) 16q (P ¼ 0.0003, Lod ¼ 2.22) 15q (Lod ¼ 2.56; genomewide empirical P ¼ 0.05) 2q (HLod ¼ 4.19; genomewide empirical P ¼ 0.02 with sex-specific recombination fractions) 4q (genomewide P < 0.05) PD AG PD AG PD AG ‘‘PD syndrome’’ PD Simple phobia Social phobia Severe panic attack or PD 1 60 25 14 17 120 19 Panic/phobic cluster score Same family sample; Lod, logarithm of odds; PD, panic disorder; AG, agoraphobia; ‘‘PD syndrome’’, phenotype of PD with or without bladder/kidney problems, mitral valve prolapse, migraine headache, thyroid problems. ARTICLE Association analyses, which examine the co-occurrence of a phenotype with specific genetic variants, have become the predominant method for identifying susceptibility loci for complex traits. identifying true association requires that the alleles studied include variants that are either directly related to the phenotype or strongly correlated with (i.e., in linkage disequilibrium with) such causal variants. Two approaches to association analysis are now feasible: (1) candidate gene studies, in which loci hypothesized to be causally related to the phenotype based on prior biological or genomic evidence are examined, and (2) whole genome association studies, in which a large number (e.g., 500,000 or more) markers designed to capture genetic variation across the entire genome, are examined. The latter approach has been used successfully in the past 2 years to identify susceptibility loci underlying a range of medical disorders. To date, however, association studies of panic and phobic disorders have been limited to the candidate gene method. Many association findings in anxiety disorders and psychiatry more broadly have been difficult to replicate. The limited understanding of the biology of these disorders means hat the prior probability that any candidate is an actual susceptibility locus is small; thus many reported associations are likely to be false positives. Furthermore, it is increasingly clear that very large samples are needed to detect robust associations given the modest effect sizes of individual susceptibility loci. As a result, it is likely that most studies to date have been underpowered, raising the risk of false negatives as well. Association analyses of PD have implicated several genes; few have been supported by independent studies. Genes reported to be associated with PD in more than one sample include catechol-o-methyl transferase (COMT) AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) [Hamilton et al., 2002; Domschke et al., 2004; Woo et al., 2004; Rothe et al., 2006], adenosine 2A receptor (ADORA2A) [Deckert et al., 1998; Hamilton et al., 2004], cholecystokinin (CCK) [Wang et al., 1998; Hattori et al., 2001; Maron et al., 2005], CCK-B receptor (CCK-B) [Kennedy et al., 1999], serotonin 2A receptor (HTR2A) [Inada et al., 2003; Maron et al., 2005], and monoamine oxidase A (MAO-A) [Deckert et al., 1999; Maron et al., 2004; Samochowiec et al., 2004]. However, in some cases, different alleles of these genes have been associated in different studies, negative studies of these genes have also been reported, and none has been established as a PD susceptibility gene. Fewer candidate gene studies of phobic disorders have appeared, though reports of association with COMT [McGrath et al., 2004], MAOA [Samochowiec et al., 2004], and the dopamine transporter (DAT1) [Rowe et al., 1998] have appeared. To date, however, no genes have been associated with phobias in independent samples. BEYOND THE DSM CATEGORIES As reviewed above, genetic epidemiologic studies have shown that genes contribute to the development of panic disorder and the phobic disorders, but no specific susceptibility genes have been established to date. Genetic studies of these phenotypes must confront two formidable obstacles related to the complexity of the anxiety disorders. The first issue relates to genetic complexity—that is, these disorders are likely to reflect the additive or interactive effect of multiple loci of small individual effect. Genetic studies of these phenotypes must confront two formidable obstacles related to the complexity of the anxiety disorders. The first issue relates to genetic complexity—that is, 121 these disorders are likely to reflect the additive or interactive effect of multiple loci of small individual effect. As a result, association studies will require much larger sample sizes than have been studied to date. The second challenge is phenotypic complexity— that is, while the DSM-defined disorders have been useful for clinical purposes, it is not clear that they are optimal for the purposes of gene finding. Indeed, evidence from a range of studies suggests that genetic influences transcend the boundaries of the DSM categories. The second challenge is phenotypic complexity—that is, while the DSM-defined disorders have been useful for clinical purposes, it is not clear that they are optimal for the purposes of gene finding. Indeed, evidence from a range of studies suggests that genetic influences transcend the boundaries of the DSM categories. As shown in Table I, family studies suggest that relatives are at greatest risk for the proband’s anxiety disorder. However, there is also evidence of significant familial co-aggregation of panic and phobic disorders. In their analysis of the large Virginia twin sample, Hettema et al.  found that the structure of genetic and environmental influences on the anxiety disorders were not isomorphic with the clinically defined categories. Using structural equation modeling, they identified two genetic factors underlying the disorders: one factor primarily predisposing to PD, agoraphobia, and GAD and the second primarily influencing 122 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) specific phobias. Social phobia was influenced by both broad factors. Molecular genetic studies have supported this evidence that genetic effects on panic and phobic disorders transcend diagnostic boundaries [Smoller et al., 2001; Kaabi et al., 2006]. Smoller et al. found suggestive evidence of linkage to a locus on chromosome 10q for a phenotype comprising PD and other anxiety disorders. In another linkage analysis, Kaabi et al.  observed significant linkage on chromosome 4q for a phenotype comprising PD, agoraphobia, social phobia and specific phobia. In addition, several candidate genes (e.g., COMT, MAO-A) have been associated with both panic and phobic anxiety [Deckert et al., 1999; Woo et al., 2002; Domschke et al., 2004; McGrath et al., 2004; Samochowiec et al., 2004], and the glutamic acid decarboxylase 1 (GAD1) gene was reported to show association with a genetic liability underlying PD, GAD, phobias, MDD, and the anxiety-related personality trait of neuroticism [Hettema et al., 2006a]. These and other studies have suggested that genes that influence anxietyrelated traits may underlie multiple anxiety disorders. Fear-conditioining, a trait central to the development of phobic disorders, is itself heritable (estimated heritability 0.35–0.55), although the genes influencing fear conditioning appear to be distinct from those underlying phobic fears [Hettema et al., 2003, 2007]. The personality traits introversion (low extraversion) and neuroticism have an estimated heritability of 0.30– 0.50 and are elevated among individuals with panic and phobic anxiety disorders and may underlie the comorbidity of these disorders and major depression [Bienvenu et al., 2001]. Introversion is characterized by low levels of sociability, high levels of arousal, and a relatively low propensity to experience positive emotions, while neuroticism indexes negative affectivity or the tendency to experience negative emotions (anxiety, sadness, anger). While neuroticism appears to be non-specifically associated with a range of anxiety disorders and depression [Hettema et al., 2006b], introversion may be more directly related to social phobia and agoraphobia. [Bienvenu et al., 2004]. In a large twin sample, Bienvenu et al.  examined genetic In a large twin sample, Bienvenu et al. examined genetic correlations between phobic disorders and two anxiety-related personality traits: neuroticism and introversion (low extraversion). They found that the genetic determinants of these personality traits entirely accounted for the genetic influences on social phobia and agoraphobia. correlations between phobic disorders and two anxiety-related personality traits: neuroticism and introversion (low extraversion). They found that the genetic determinants of these personality traits entirely accounted for the genetic influences on social phobia and agoraphobia. In other words, there were no genetic risk factors for these phobias over and above those underlying the personality traits. In contrast, the genes influencing animal phobia (a specific phobia) appeared to be largely distinct from those influencing the personality traits. The anxiety-related trait of harm avoidance has also been implicated in panic and phobic disorders. Individuals scoring high on harm avoidance are fearful, socially inhibited, easily tired, and pessimistic [Cloninger, 1986]. Harm avoidance is elevated among patients with anxiety disorders [Starcevic et al., 1996; Lyoo et al., 2001; Rettew et al., 2006; Faytout et al., 2007] and in their relatives [Stein et al., 2001]. The possibility that these anxietyrelated traits represent ‘‘intermediate phenotypes’’ that are more proximal to gene effects than are the complex clinical diagnoses has motivated linkage and association studies of these phenotypes. ARTICLE The possibility that these anxiety-related traits represent ‘‘intermediate phenotypes’’ that are more proximal to gene effects than are the complex clinical diagnoses has motivated linkage and association studies of these phenotypes. Linkage has been reported for neuroticism to five chromosomal regions, including a region on chromosome 1q syntenic with a region of mouse chromosome 1 that has been strongly linked to anxiety/fear behavior [Fullerton et al., 2003], and harm avoidance has been linked to regions on chromosome 8p [Cloninger et al., 1998; Zohar et al., 2003; Dina et al., 2005]. Several candidate gene association studies have implicated specific genetic variants in neuroticism or harm avoidance, including the short allele of the serotonin transporter 5HTTLPR polymorphism. However, three meta-analyses of these studies [Schinka et al., 2004; Sen et al., 2004; Munafo et al., 2005] have reached conflicting conclusions. A recent genomewide association study failed to detect any loci explaining more than 1% of the variance in the trait [Shifman et al., 2007]. The temperamental profile known as behavioral inhibition to the unfamiliar (BI) has been implicated as a familial and developmental risk factor for panic and phobic disorders (see Hirshfeld-Becker The temperamental profile known as behavioral inhibition to the unfamiliar (BI) has been implicated as a familial and developmental risk factor for panic and phobic disorders. ARTICLE et al., this issue). BI is observable in laboratory-based assessments as early as infancy and consists of a stable tendency to be cautious, quiet, and behaviorally restrained in situations of novelty [Kagan et al., 1988]. Longitudinal and crosssectional studies that have supported the conclusion that BI is a developmental risk factor for social phobia, panic and other anxiety disorder symptomatology [Kochanska and Radke-Yarrow, 1992; Hayward et al., 1998; Mick and Telch, 1998; Schwartz et al., 1999; Wittchen et al., 1999; Muris et al., 2001]. Estimates of the heritability of BI have ranged from 0.41 to 0.76, with estimates as high as >0.9 for extreme BI [Matheny, 1989; Robinson et al., 1992; Plomin et al., 1993; DiLalla et al., 1994; Goldsmith and Lemery, 2000; Eley et al., 2003]. A series of studies have demonstrated elevated rates of BI among offspring of parents with panic disorder with or without agoraphobia [Rosenbaum et al., 1988; Rosenbaum et al., 2000] and an elevated risk of social phobia, multiple anxiety disorders, and chronicity of anxiety disorders among parents of children with BI [Rosenbaum et al., 1991, 1992]. Longitudinal studies have demonstrated that BI is a developmental risk factor for social phobia [Schwartz et al., 1999; Hirshfeld-Becker et al., 2007]. Neurobiologic correlates of BI include evidence of sympathetic and HPA axis activation, EEG evidence of right frontal cortical activation, and amygdala hyper-reactivity to novelty [Schwartz et al., 2003; Fox et al., 2005a]. Genetic association studies have begun to implicate several genes that may influence the BI phenotype, including the corticotropin releasing hormone gene (CRH) [Smoller et al., 2005] and the serotonin transporter (SLC6A4) [Fox et al., 2005b]. Animal models suggest that the BI phenotype is observed across phylogenies, including rodents and primates [Kalin, 2004; Willis-Owen and Flint, 2006]. Genetic studies of mouse models of anxious temperament have suggested candidate loci relevant to anxious temperament. In particular, the gene encoding regulator of G-protein signaling 2 (Rgs2) has been identified as a quantitative trait gene AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) influencing BI-like phenotypes in mice [Yalcin et al., 2004]. Smoller et al.  recently provided evidence that the human ortholog RGS2 is associated with BI and other intermediate phenotypes underlying social phobia. Alleles of markers spanning RGS2 were strongly associated with childhood BI (OR ¼ 2.99) and were also associated with introversion in adults and with increased limbic activation (insular cortex and amygdala) during emotion processing (brain phenotypes correlated with social phobia). Such findings suggest that translational studies bringing together insights from comparative genomics, as well as behavioral and neuroimaging intermediate phenotypes may help unravel the genetic basis of anxiety disorders. CONCLUSIONS It is clear that genetic factors influence risk for panic and phobic disorders, but identifying the specific genes involved has been challenging given the genetic and phenotypic complexity of these conditions. The recent discovery of susceptibility genes for other complex medical disorders (e.g., diabetes, rheumatoid arthritis, heart disease, and inflammatory bowel disease) provides important proof that genes can be found despite such complexity. However, these successes required genomewide association methods and much larger samples than have been included in studies of anxiety disorders. In addition to the need for such large-scale studies, genetic investigations of panic and phobic anxiety disorders should exploit the particular opportunities that exist relevant to these disorders: namely, the availability of well-characterized animal models and putative intermediate phenotypes that have been robustly associated with the development and biology of anxiety disorders. Gene mapping and gene targeting studies in mice have implicated specific genes influencing anxious temperament and conditioned fear behavior [Finn et al., 2003; Willis-Owen and Flint, 2006], and human studies have identified behavioral and neuroimaging 123 phenotypes that reflect fundamental components of panic and phobic disorders and that are under genetic influence [Etkin and Wager, 2007; Munafo et al., 2007; Smoller et al., 2008]. These advances provide cause for optimism that the coming years will see significant progress in understanding the genetic basis of panic and phobic anxiety disorders. REFERENCES Albert CM, Chae CU, Rexrode KM, Manson JE, Kawachi I. 2005. Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 111:480– 487. Bienvenu OJ, Brown C, Samuels JF, Liang KY, Costa PT, Eaton WW, Nestadt G. 2001. Normal personality traits and comorbidity among phobic, panic and major depressive disorders. Psychiatry Res 102:73–85. Bienvenu OJ, Samuels JF, Costa PT, Reti IM, Eaton WW, Nestadt G. 2004. Anxiety and depressive disorders and the five-factor model of personality: A higher- and lowerorder personality trait investigation in a community sample. Depress Anxiety 20: 92–97. Bienvenu OJ, Hettema JM, Neale MC, Prescott CA, Kendler KS. 2007. Low extraversion and high neuroticism as indices of genetic and environmental risk for social phobia, agoraphobia, and animal phobia. Am J Psychiatry 164:1714–1721. Cloninger C. 1986. A unified biosocial theory of personality and its role in the development of anxiety states. Psychiatr Dev 3:167–226. Cloninger CR, Van Eerdewegh P, Goate A, Edenberg HJ, Blangero J, Hesselbrock V, Reich T, Nurnberger J Jr, Schuckit M, Porjesz B, Crowe R, Rice JP, Foroud T, Przybeck TR, Almasy L, Bucholz K, Wu W, Shears S, Carr K, Crose C, Willig C, Zhao J, Tischfield JA, Li TK, Conneally PM, Begleiter H. 1998. Anxiety proneness linked to epistatic loci in genome scan of human personality traits. Am J Med Genet 81:313– 317. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R Jr. 2001. Genomewide survey of panic disorder. Am J Med Genet 105:105–109. Deckert J, Nothen M, Franke P, Delmo C, Fritze J, Knapp M, Maier W, Beckmann H, Propping P. 1998. Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 3:81–85. Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nothen MM, Maffei P, Franke P, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Lesch KP. 1999. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 8:621–624. 124 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) DiLalla L, Kagan J, Reznick J. 1994. Genetic etiology of behavioral inhibition among 2-year-old children. Infant Behav Dev 17: 405–412. Dina C, Nemanov L, Gritsenko I, Rosolio N, Osher Y, Heresco-Levy U, Sariashvilli E, Bachner-Melman R, Zohar AH, Benjamin J, Belmaker RH, Ebstein RP. 2005. Fine mapping of a region on chromosome 8p gives evidence for a QTL contributing to individual differences in an anxiety-related personality trait: TPQ harm avoidance. Am J Med Genet Part B Neuropsychiatr Genet 132B:104–108. Domschke K, Freitag CM, Kuhlenbaumer G, Schirmacher A, Sand P, Nyhuis P, Jacob C, Fritze J, Franke P, Rietschel M, Garritsen HS, Fimmers R, Nöthen MM, Lesch KP, Stögbauer F, Deckert J. 2004. Association of the functional V158M catechol-O-methyltransferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 7:183–188. Eley TC, Bolton D, O’Connor TG, Perrin S, Smith P, Plomin R. 2003. A twin study of anxiety-related behaviours in pre-school children. J Child Psychol Psychiatry 44: 945–960. Etkin A, Wager TD. 2007. Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164:1476–1488. Faytout M, Tignol J, Swendsen J, Grabot D, Aouizerate B, Lepine JP. 2007. Social phobia, fear of negative evaluation and harm avoidance. Eur Psychiatry 22:75–79. Finn DA, Rutledge-Gorman MT, Crabbe JC. 2003. Genetic animal models of anxiety. Neurogenetics 4:109–135. Fox NA, Henderson HA, Marshall PJ, Nichols KE, Ghera MM. 2005a. Behavioral inhibition: Linking biology and behavior within a developmental framework. Annu Rev Psychol 56:235–262. Fox NA, Nichols KE, Henderson HA, Rubin K, Schmidt L, Hamer D, Ernst M, Pine DS. 2005b. Evidence for a gene-environment interaction in predicting behavioral inhibition in middle childhood. Psychol Sci 16: 921–926. Fullerton J, Cubin M, Tiwari H, Wang C, Bomhra A, Davidson S, Miller S, Fairburn C, Goodwin G, Neale MC, Fiddy S, Mott R, Allison DB, Flint J. 2003. Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitativetrait loci that influence variation in the human personality trait neuroticism. Am J Hum Genet 72:879–890. Fyer A, Mannuzza S, Chapman T, Liebowitz M, Klein D. 1993. A direct interview family study of social phobia. Arch Gen Psychiatry 50:286–293. Fyer AJ, Mannuzza S, Chapman TF, Martin LY, Klein DF. 1995. Specificity in familial aggregation of phobic disorders. Arch Gen Psychiatry 52:564–573. Fyer A, Manuzza S, Chapman T, Lipsitz J, Martin L, Klein D. 1996. Panic disorder and social phobia: Effects of comorbidity on familial transmission. Anxiety 2:173–178. Fyer AJ, Hamilton SP, Durner M, Haghighi F, Heiman GA, Costa R, Evgrafov O, Adams P, de Leon AB, Taveras N, Klein DF, Hodge SE, Weissman MM, Knowles JA. 2006. A third-pass genome scan in panic disorder: Evidence for multiple susceptibility loci. Biol Psychiatry 60:388–401. Gelernter J, Bonvicini K, Page G, Woods SW, Goddard AW, Kruger S, Pauls DL, Goodson S. 2001. Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am J Med Genet 105:548–557. Gelernter J, Page GP, Bonvicini K, Woods SW, Pauls DL, Kruger S. 2003. A chromosome 14 risk locus for simple phobia: Results from a genomewide linkage scan. Mol Psychiatry 8:71–82. Gelernter J, Page GP, Stein MB, Woods SW. 2004. Genome-wide linkage scan for loci predisposing to social phobia: Evidence for a chromosome 16 risk locus. Am J Psychiatry 161:59–66. Goldsmith HH, Lemery KS. 2000. Linking temperamental fearfulness and anxiety symptoms: A behavior-genetic perspective. Biol Psychiatry 48:1199–1209. Goldstein RB, Weissman MM, Adams PB, Horwath E, Lish JD, Charney D, Woods SW, Sobin C, Wickramaratne PJ. 1994. Psychiatric disorders in relatives of probands with panic disorder and/or major depression. Arch Gen Psychiatry 51:383–394. Goldstein R, Wickramaratne P, Horwath E, Weissman M. 1997. Familial aggregation and phenomenology of ‘early’-onset (at or before age 20 years) panic disorder. Arch Gen Psychiatry 54:271–278. Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JR, Ballenger JC, Fyer AJ. 1999. The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry 60:427–435. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. 2002. Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry 51: 591–601. Hamilton SP, Fyer AJ, Durner M, Heiman GA, Baisre de Leon A, Hodge SE, Knowles JA, Weissman MM. 2003. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Natl Acad Sci USA 100:2550–2555. Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. 2004. Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology 29: 558–565. Hattori E, Ebihara M, Yamada K, Ohba H, Shibuya H, Yoshikawa T. 2001. Identification of a compound short tandem repeat stretch in the 5’-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia. Mol Psychiatry 6:465–470. Hayward C, Killen J, Kraemer H, Taylor C. 1998. Linking self-reported childhood behavioral inhibition to adolescent social phobia. J Am Acad Child Adolesc Psychiatry 37:1308– 1316. Hettema JM, Neale MC, Kendler KS. 2001. A review and meta-analysis of the genetic ARTICLE epidemiology of anxiety disorders. Am J Psychiatry 158:1568–1578. Hettema JM, Annas P, Neale MC, Kendler KS, Fredrikson M. 2003. A twin study of the genetics of fear conditioning. Arch Gen Psychiatry 60:702–708. Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. 2005. The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry 62:182–189. Hettema JM, An SS, Neale MC, Bukszar J, van den Oord EJ, Kendler KS, Chen X. 2006a. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry 11:752–762. Hettema JM, Neale MC, Myers JM, Prescott CA, Kendler KS. 2006b. A population-based twin study of the relationship between neuroticism and internalizing disorders. Am J Psychiatry 163:857–864. Hettema JM, Annas P, Neale MC, Fredrikson M, Kendler KS. 2007. The genetic covariation between fear conditioning and self-report fears. Biol Psychiatry (in press). Hirshfeld-Becker DR, Biederman J, Henin A, Faraone SV, Davis S, Harrington K, Rosenbaum JF. 2007. Behavioral inhibition in preschool children at risk is a specific predictor of middle childhood social anxiety: A five-year follow-up. J Dev Behav Pediatr 28:225–323. Horwath E, Wolk SI, Goldstein RB, Wickramaratne P, Sobin C, Adams P, Lish JD, Weissman MM. 1995. Is the comorbidity between social phobia and panic disorder due to familial cotransmission or other factors? Arch Gen Psychiatry 52:574–582. Inada Y, Yoneda H, Koh J, Sakai J, Himei A, Kinoshita Y, Akabame K, Hiraoka Y, Sakai T. 2003. Positive association between panic disorder and polymorphism of the serotonin 2A receptor gene. Psychiatry Res 118:25– 31. Kaabi B, Gelernter J, Woods SW, Goddard A, Page GP, Elston RC. 2006. Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: Strong evidence for a chromosome 4 risk locus. Am J Hum Genet 78:543–553. Kagan J, Reznick S, Snidman N. 1988. Biological bases of childhood shyness. Science 240: 167–171. Kalin NH. 2004. Studying non-human primates: A gateway to understanding anxiety disorders. Psychopharmacol Bull 38:8–13. Kennedy JL, Bradwejn J, Koszycki D, King N, Crowe R, Vincent J, Fourie O. 1999. Investigation of cholecystokinin system genes in panic disorder. Mol Psychiatry 4:284–285. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. 2005. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593–602. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters EE. 2006. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry 63:415– 424. ARTICLE Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA, Haghighi F, de Jesus GM, Rassnick H, Preud’hommeRivelli X, Austin T, Cunjak J, Mick S, Fine LD, Woodley KA, Das K, Maier W, Adams PB, Freimer NB, Klein DF, Gilliam TC. 1998. Results of a genome-wide genetic screen for panic disorder. Am J Med Genet 81:139–147. Kochanska G, Radke-Yarrow M. 1992. Inhibition in toddlerhood and the dynamics of the child’s interaction with an unfamiliar peer at age five. Child Dev 63:325–335. Lyoo IK, Lee DW, Kim YS, Kong SW, Kwon JS. 2001. Patterns of temperament and character in subjects with obsessive-compulsive disorder. J Clin Psychiatry 62:637–641. Maier W, Minges J, Lichtermann D. 1995. The familial relationship between panic disorder and unipolar depression. J Psychiat Res 29: 375–388. Maron E, Tasa G, Toru I, Lang A, Vasar V, Shlik J. 2004. Association between serotoninrelated genetic polymorphisms and CCK4-induced panic attacks with or without 5hydroxytryptophan pretreatment in healthy volunteers. World J Biol Psychiatry 5:149– 154. Maron E, Nikopensius T, Koks S, Altmae S, Heinaste E, Vabrit K, Tammekivi V, Hallast P, Koido K, Kurg A, Metspalu A, Vasar E, Vasar V, Shlik J. 2005. Association study of 90 candidate gene polymorphisms in panic disorder. Psychiatr Genet 15:17–24. Matheny AP Jr. 1989. Children’s behavioral inhibition over age and across situations: Genetic similarity for a trait during change. J Personality 57:215–235. McGrath M, Kawachi I, Ascherio A, Colditz GA, Hunter DJ, De Vivo I. 2004. Association between catechol-O-methyltransferase and phobic anxiety. Am J Psychiatry 161:1703– 1705. Mendlewicz J, Papdimitriou G, Wilmotte J. 1993. Family study of panic disorder: Comparison with generalized anxiety disorder, major depression and normal subjects. Psychiatr Genet 3:73–78. Mick MA, Telch MJ. 1998. Social anxiety and history of behavioral inhibition in young adults. J Anxiety Disord 12:1–20. Munafo MR, Clark T, Flint J. 2005. Does measurement instrument moderate the association between the serotonin transporter gene and anxiety-related personality traits? A meta-analysis. Mol Psychiatry 10:415– 419. Munafo MR, Brown SM, Hariri AR. 2007. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: A metaanalysis. Biol Psychiatry (in press). Muris P, Merckelbach H, Schmidt H, Gadet BB, Bogie N. 2001. Anxiety and depression as correlates of self-reported behavioural inhibition in normal adolescents. Behav Res Ther 39:1051–1061. Noyes R Jr, Crowe RR, Harris EL, Hampa BJ, McChesney CM, Chaudry DR. 1986. Relationship between panic disorder and agoraphobia: A family study. Arch Gen Psychiatry 43:227–232. Plomin R, Emde R, Braungart J, Campos J, Corley R, Fulker D, Kagan J, Reznick J, Robinson J, Zahn-Waxler C, et al. 1993. AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) Genetic change and continuity from fourteen to twenty months: The MacArthur Longitudinal Twin Study. Child Dev 64: 1354–1376. Rettew DC, Doyle AC, Kwan M, Stanger C, Hudziak JJ. 2006. Exploring the boundary between temperament and generalized anxiety disorder: A receiver operating characteristic analysis. J Anxiety Disord 20:931–945. Robinson J, Kagan J, Reznick J, Corley R. 1992. The heritability of inhibited and uninhibited behavior: A twin study. Dev Psychol 28: 1030–1037. Rosenbaum J, Biederman J, Gersten M, Hirshfeld D, Meminger S, Herman J, Kagan J, Reznick J, Snidman N. 1988. Behavioral inhibition in children of parents with panic disorder and agoraphobia: A controlled study. Arch Gen Psychiatry 45:463–470. Rosenbaum J, Biederman J, Hirshfeld D, Bolduc E, Faraone S, Kagan J, Snidman N, Reznick J. 1991. Further evidence of an association between behavioral inhibition and anxiety disorders: Results from a family study of children from a non-clinical sample. J Psychiatr Res 25:49–65. Rosenbaum JF, Biederman J, Bolduc EA, Hirshfeld DR, Faraone SV, Kagan J. 1992. Comorbidity of parental anxiety disorders as risk for childhood-onset anxiety in inhibited children. Am J Psychiatry 149: 475–481. Rosenbaum JF, Biederman J, Hirshfeld-Becker DR, Kagan J, Snidman N, Friedman D, Nineberg A, Gallery DJ, Faraone SV. 2000. A controlled study of behavioral inhibition in children of parents with panic disorder and depression. Am J Psychiatry 157:2002– 2010. Rothe C, Koszycki D, Bradwejn J, King N, Deluca V, Tharmalingam S, Macciardi F, Deckert J, Kennedy JL. 2006. Association of the Val158Met catechol O-methyltransferase genetic polymorphism with panic disorder. Neuropsychopharmacology 31: 2237–2242. Rowe D, Stever C, Gard J, Cleveland H, Sanders M, Abramowitz A, Kozol S, Mohr J, Sherman S, Waldman I. 1998. The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children. Behav Genet 28:215–225. Samochowiec J, Hajduk A, Samochowiec A, Horodnicki J, Stepien G, Grzywacz A, Kucharska-Mazur J. 2004. Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res 128:21–26. Schinka JA, Busch RM, Robichaux-Keene N. 2004. A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Mol Psychiatry 9:197–202. Schwartz C, Snidman N, Kagan J. 1999. Adolescent social anxiety as an outcome of inhibited temperament in childhood. J Am Acad Child Adolesc Psychiatry 38:1008– 1015. Schwartz CE, Wright CI, Shin LM, Kagan J, Rauch SL. 2003. Inhibited and uninhibited infants ‘‘grown up’’: Adult amygdalar response to novelty. Science 300:1952– 1953. 125 Sen S, Burmeister M, Ghosh D. 2004. Metaanalysis of the association between a serotonin transporter promoter polymorphism (5HTTLPR) and anxiety-related personality traits. Am J Med Genet Part B Neuropsychiatr Genet 127B:85–89. Shifman S, Bhomra A, Smiley S, Wray NR, James MR, Martin NG, Hettema JM, An SS, Neale MC, van den Oord EJ, Kendler KS, Chen X, Boomsma DI, Middeldorp CM, Hottenga JJ, Slagboom PE, Flint J. 2007. A whole genome association study of neuroticism using DNA pooling. Mol Psychiatry (in press). Smoller JW, Acierno JS Jr, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, Pava JA, Chadwick LH, White C, Bulzacchelli M, Slaugenhaupt SA. 2001. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet 105:195–206. Smoller JW, Yamaki LH, Fagerness JA, Biederman J, Racette S, Laird NM, Kagan J, Snidman N, Faraone SV, Hirshfeld-Becker D, Tsuang MT, Slaugenhaupt SA, Rosenbaum JF, Sklar PB. 2005. The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. Biol Psychiatry 57:1485–1492. Smoller JW, Pollack MH, Wassertheil-Smoller S, Jackson RD, Oberman A, Wong ND, Sheps D. 2007. Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women’s Health Initiative Observational Study. Arch Gen Psychiatry 64:1153–1160. Smoller JW, Paulus MP, Fagerness JA, Purcell S, Yamaki L, Hirshfeld-Becker D, Biederman J, Rosenbaum JF, Gelernter J, Stein MB. 2008. Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch Gen Psychiatry (in press). Starcevic V, Uhlenhuth EH, Fallon S, Pathak D. 1996. Personality dimensions in panic disorder and generalized anxiety disorder. J Affect Disord 37:75–79. Stein MB, Chartier MJ, Hazen AL, Kozak MV, Tancer ME, Lander S, Furer P, Chubaty D, Walker JR. 1998. A direct-interview family study of generalized social phobia. Am J Psychiatry 155:90–97. Stein MB, Chartier MJ, Lizak MV, Jang KL. 2001. Familial aggregation of anxiety-related quantitative traits in generalized social phobia: Clues to understanding ‘disorder’ heritability? Am J Med Genet 105:79–83. Thorgeirsson TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, Kolbeinsson H, Lindal E, Gagunashvili N, Frigge ML, Kong A, Stefansson K, Gulcher JR. 2003. Anxiety with panic disorder linked to chromosome 9q in iceland. Am J Hum Genet 72:1221–1230. Wang Z, Valdes J, Noyes R, Zoega T, Crowe R. 1998. Possible association of a cholecystokinin promotor polymorphism (CCK36CT) with panic disorder. Am J Med Genet 81:228–234. Weissman M, Fyer A, Haghighi F, Heiman G, Deng Z, Hen R, Hodge S, Knowles J. 2000. Potential panic disorder syndrome: Clinical and genetic linkage evidence. Am J Med Genet 96:24–35. Willis-Owen SA, Flint J. 2006. The genetic basis of emotional behaviour in mice. Eur J Hum Genet 14:721–728. 126 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) Wittchen H-U, Stein M, Kessler R. 1999. Social fears and social phobia in a community sample of adolescents and young adults: Prevalence, risk factors and co-morbidity. Psychol Med 29:309–323. Woo JM, Yoon KS, Yu BH. 2002. Catechol Omethyltransferase genetic polymorphism in panic disorder. Am J Psychiatry 159:1785– 1787. Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH. 2004. The association between panic disorder and the L/L genotype of catecholO-methyltransferase. J Psychiatr Res 38: 365–370. Yalcin B, Willis-Owen SA, Fullerton J, Meesaq A, Deacon RM, Rawlins JN, Copley RR, Morris AP, Flint J, Mott R. 2004. Genetic dissection of a behavioral quantitative trait ARTICLE locus shows that Rgs2 modulates anxiety in mice. Nat Genet 36:1197–1202. Zohar AH, Dina C, Rosolio N, Osher Y, Gritsenko I, Bachner-Melman R, Benjamin J, Belmaker RH, Ebstein RP. 2003. Tridimensional personality questionnaire trait of harm avoidance (anxiety proneness) is linked to a locus on chromosome 8p21. Am J Med Genet Part B Neuropsychiatr Genet 117B:66–69.