Linkage analysis of alternative anxiety phenotypes in multiply affected panic disorder families

Abstract

Background The choice of phenotype definitions for genetic studies of panic and phobic disorders is complicated by family, twin and neurobiological data indicating both distinct and shared risk factors as well as heterogeneity within categories. We previously reported a genome scan in 120 multiplex panic disorder (PD) families using a phenotype that closely adhered to the DSM IV PD definition. Here we extend this work by conducting exploratory linkage analyses in this same pedigree set using ten additional literature- based panic and phobia-related phenotypes that take into account aspects of these hypothesized complexities. Methods Multiply affected families (> 2 individuals with PD) were recruited from clinical and non-clinical sources, evaluated by clinician administered semi-structured interview and subsequent blind consensus best estimate procedure. Each phenotype was analyzed under dominant and recessive models using parametric 2-point (homogeneity and heterogeneity), multipoint, and non-parametric methods. Empirically based permutations were used to estimate model specific and global (across all phenotypes) p-values. Results The highest score was a 2-point lod (4.27, global p < 0.08) on chromosome 13 (D13S793, 76cM) for the phenotype “specific or social phobia” under a recessive model and conditions of homogeneity. There was minimal support for linkage to any of the remaining nine phenotypes. Conclusions Though interpretation of findings is limited by sample size and the large number of phenotypes and models analyzed these data suggest a region on chromosome 13 as a potential site for further exploration in relation to risk for specific and social phobias.

Subcortical brain volumes, cortical thickness and cortical surface area in families genetically enriched for social anxiety disorder – A multiplex multigenerational neuroimaging study

“…With respect to the latter, the heritability of SAD is estimated to be between 39 and 56% [ [27] , [28] , [29] , [30] ]. However, despite the promising results of a handful of studies investigating the genetic background of SAD [ [30] , [31] , [32] , [33] , [34] , [35] , [36] ], the genetic variants underlying the vulnerability for SAD are at present still largely unidentified. Detecting such ‘SAD genes’ is difficult due to several factors.…”

Genetics of social anxiety disorder: a systematic review

“…A few investigators performed linkage analysis in SAD (Stein et al , 1998a, Gelernter et al , 2004; Fyer et al , 2012). Gelernter et al (2004) found a linkage on chromosome 16 at position 71.1, with a LOD score of 2.22 between D16S415 and D16S503 (Gelernter et al , 2004).…”

“…Fyer et al (2012) conducted linkage analysis in families affected by panic disorder and found that linkage signal on chromosome 13 for specific and social phobia phenotype (Fyer et al , 2012). The highest LODs score was 4.27 ( P < 0.08) chromosome 13 (D13S793, 76cM) using both social and specific phobia.…”

“…Binelli et al (2015) reported significant inverse relationships of the SLC6A4 STin2.VNTR genotype frequency but not 5-HTTLPR between harm avoidance and novelty seeking subgroups of 142 students with SAD (P = 0.005), implicating the presence of different subgroups in SAD (Binelli et al, 2015). The high harm avoidance and low novelty seeking subgroup had a higher frequency of the STin2.VNTR 1010/1012 genotype, while the high harm avoidance and high novelty seeking subgroup had None of the 24 SNPs and variants that were tested showed an association with SAD in case-control sample after Bonferroni correction 2 SNPs showed significance: rs818702 (P = 0.032) and rs140701 (P = 0.048) SAD cases without PD showed 2 SNPs, rs140701 (P = 0.021) and rs12576775 (P = 0.028) in association with SAD-Quantitative analysis of SAD symptom severity was found to be nominally associated with 4 SNPs, rs10994359, rs818702, rs1133503 and rs2306073 (strongest signal P = 0.001 but corrected P = 0.136 for rs10994359) rs10994359, located near the ANK3 gene, is also nominally associated with high harm avoidance scores (P = 0.001 with corrected P = 0.083) Fyer et al, 2012 120 multiplex panic disorder (PD) families For social phobia specifically, there were 61 families, and 213 affected individuals out of 609 Families were recruited from both clinical and nonclinical sources -families must have had 3 affected members willing to be interviewed and provide blood sample for genotyping All were interviewed using the SADS-LA…”

“…Gelernter et al (2004) found a linkage on chromosome 16 at position 71.1, with a LOD score of 2.22 between D16S415 and D16S503 (Gelernter et al, 2004). Fyer et al (2012) conducted linkage analysis in families affected by panic disorder and found that linkage signal on chromosome 13 for specific and social phobia phenotype (Fyer et al, 2012). The highest LODs score was 4.27 (P < 0.08) chromosome 13 (D13S793, 76cM) using both social and specific phobia.…”