TY - JOUR
T1 - Risk gene-set and pathways in 22q11.2 deletion-related schizophrenia
T2 - a genealogical molecular approach
AU - Michaelovsky, Elena
AU - Carmel, Miri
AU - Frisch, Amos
AU - Salmon-Divon, Mali
AU - Pasmanik-Chor, Metsada
AU - Weizman, Abraham
AU - Gothelf, Doron
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The 22q11.2 deletion is a strong, but insufficient, “first hit” genetic risk factor for schizophrenia (SZ). We attempted to identify “second hits” from the entire genome in a unique multiplex 22q11.2 deletion syndrome (DS) family. Bioinformatic analysis of whole-exome sequencing and comparative-genomic hybridization array identified de novo and inherited, rare and damaging variants, including copy number variations, outside the 22q11.2 region. A specific 22q11.2-haplotype was associated with psychosis. The interaction of the identified “second hits” with the 22q11.2 haploinsufficiency may affect neurodevelopmental processes, including neuron projection, cytoskeleton activity, and histone modification in 22q11.2DS-ralated psychosis. A larger load of variants, involved in neurodevelopment, in combination with additional molecular events that affect sensory perception, olfactory transduction and G-protein-coupled receptor signaling may account for the development of 22q11.2DS-related SZ. Comprehensive analysis of multiplex families is a promising approach to the elucidation of the molecular pathophysiology of 22q11.2DS-related SZ with potential relevance to treatment.
AB - The 22q11.2 deletion is a strong, but insufficient, “first hit” genetic risk factor for schizophrenia (SZ). We attempted to identify “second hits” from the entire genome in a unique multiplex 22q11.2 deletion syndrome (DS) family. Bioinformatic analysis of whole-exome sequencing and comparative-genomic hybridization array identified de novo and inherited, rare and damaging variants, including copy number variations, outside the 22q11.2 region. A specific 22q11.2-haplotype was associated with psychosis. The interaction of the identified “second hits” with the 22q11.2 haploinsufficiency may affect neurodevelopmental processes, including neuron projection, cytoskeleton activity, and histone modification in 22q11.2DS-ralated psychosis. A larger load of variants, involved in neurodevelopment, in combination with additional molecular events that affect sensory perception, olfactory transduction and G-protein-coupled receptor signaling may account for the development of 22q11.2DS-related SZ. Comprehensive analysis of multiplex families is a promising approach to the elucidation of the molecular pathophysiology of 22q11.2DS-related SZ with potential relevance to treatment.
UR - http://www.scopus.com/inward/record.url?scp=85060934070&partnerID=8YFLogxK
U2 - 10.1038/s41398-018-0354-9
DO - 10.1038/s41398-018-0354-9
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AN - SCOPUS:85060934070
SN - 2158-3188
VL - 9
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 15
ER -