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

被引:6
作者
Halvorsen, Matthew [1 ]
Szatkiewicz, Jin [1 ]
Mudgal, Poorva [1 ]
Yu, Dongmei [2 ,3 ]
Nordsletten, Ashley E. [4 ,5 ]
Mataix-Cols, David [4 ]
Mathews, Carol A. [6 ,7 ]
Scharf, Jeremiah M. [2 ,3 ,8 ]
Mattheisen, Manuel [4 ,9 ,10 ,11 ]
Robertson, Mary M. [12 ]
McQuillin, Andrew [13 ]
Crowley, James J. [1 ,4 ,14 ]
机构
[1] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA
[2] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Ctr Genom Med, Boston, MA 02114 USA
[3] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA
[4] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden
[5] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA
[6] Univ Florida, Dept Psychiat, Gainesville, FL 32611 USA
[7] Univ Florida, Genet Inst, Gainesville, FL USA
[8] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA
[9] Aarhus Univ, Dept Biomed, Aarhus, Denmark
[10] Stockholm Cty Council, Ctr Psychiat Res, Stockholm Hlth Care Serv, Stockholm, Sweden
[11] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany
[12] UCL, London, England
[13] UCL, Div Psychiat, Mol Psychiat Lab, London, England
[14] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA
基金
瑞典研究理事会;
关键词
LINKAGE ANALYSIS; TIC DISORDERS; HISTIDINE-DECARBOXYLASE; SUSCEPTIBILITY; NEURORECEPTOR; TRANSMISSION; ASSOCIATION; EXCLUSION; DELETION; SLITRK1;
D O I
10.1038/s41380-021-01277-w
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:7522 / 7529
页数:8
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