Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree

Abstract

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as "cases" (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and five with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases, and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

Figure 1.

The pedigree for the family being studied. The plus signs indicate individuals where we were able to obtain DNA and conduct array-based genotyping. Individuals being pointed to with an arrow were subjected to whole genome sequencing. We highlight inbreeding loops which represent potential means through which recessive genotypes or polygenic risk for Tourette syndrome could accumulate.

Figure 2.

Manhattan plots for single locus and variant tests in affected pedigree members versus unaffected controls. We were unable to identify a single array IBD segment (top), array CNV (middle) or WGS SNV/indel/CNV (bottom) which was found in cases relative to controls at a degree of significance that survives multiple testing. This is not to say that there is no contribution of risk from rare variants within this particular pedigree, but rather that we lack evidence for a particular single rare variant contributing to risk in the pedigree.

Figure 3.

Comparisons of common variant genetic risk scores for Tourette syndrome in unrelated controls (n=2832), unrelated TS cases (n=2171), unaffected family members (n=22) and affected family members (n=43). We noted that affected family members had a significantly higher TS GRS than controls (P=5.22×10⁻⁵). There was not significant evidence for a difference in TS GRS between unaffected family members and controls (P=0.23)..