TY - JOUR
T1 - The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism
T2 - Association study and meta-analysis
AU - Gruenblatt, Edna
AU - Nemoda, Zsofia
AU - Werling, Anna Maria
AU - Roth, Alexander
AU - Angyal, Nora
AU - Tarnok, Zsanett
AU - Thomsen, Hauke
AU - Peters, Triinu
AU - Hinney, Anke
AU - Hebebrand, Johannes
AU - Lesch, Klaus-Peter
AU - Romanos, Marcel
AU - Walitza, Susanne
N1 - Funding Information:
The authors thank the families, patients, and control volunteers who participated in this research. The authors would like to acknowledge Psychiatric Genomics Consortium (PGC) ADHD for providing us with the newest summary statistics of the GWAS, Ms. Miryame Hofmann and Mrs. Susanne Kunert-Dümpelmann for their laboratory technical support. The authors acknowledge the national grant that supported the Hungarian study (NAP-B KTIA_NAP_13-2014-0011), the Deutsche Forschungsgemeinschaft (DFG) grant that supported the German study (KFO125; HE1446/9-1, HI865/2-1) and the
Funding Information:
information Hungarian Brain Research Program, Grant/Award Number: NAP-B KTIA_NAP_13-2014-0011; University of Zurich, Filling the Gap, Grant/Award Number: Postdoctoral to Anna Maria Werling; University of Zurich; Deutsche Forschungsgemeinschaft, Grant/Award Number: HE1446/9-1HI865/2-1KFO125The authors thank the families, patients, and control volunteers who participated in this research. The authors would like to acknowledge Psychiatric Genomics Consortium (PGC) ADHD for providing us with the newest summary statistics of the GWAS, Ms. Miryame Hofmann and Mrs. Susanne Kunert-D?mpelmann for their laboratory technical support. The authors acknowledge the national grant that supported the Hungarian study (NAP-B KTIA_NAP_13-2014-0011), the Deutsche Forschungsgemeinschaft (DFG) grant that supported the German study (KFO125; HE1446/9-1, HI865/2-1) and the postdoctoral grant support for Anna Maria Werling by the University of Zurich, the ?Filling the Gap program?.
Publisher Copyright:
© 2018 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.
PY - 2019/9
Y1 - 2019/9
N2 - Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta-analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets.
AB - Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta-analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets.
KW - attention-deficit hyperactivity disorder
KW - gender
KW - genetics
KW - polymorphism
KW - SNP
KW - GENOME-WIDE ASSOCIATION
KW - DEFICIT HYPERACTIVITY DISORDER
KW - BONE-MINERAL DENSITY
KW - NEURAL-TUBE DEFECTS
KW - FUNCTIONAL ANNOTATION
KW - BIPOLAR DISORDER
KW - OVERLAP
KW - RISK
KW - LOW-DENSITY-LIPOPROTEIN-RECEPTOR-RELATED-PROTEIN-6
KW - DIFFERENTIATION
U2 - 10.1002/ajmg.b.32695
DO - 10.1002/ajmg.b.32695
M3 - Article
C2 - 30474181
SN - 1552-4841
VL - 180
SP - 365
EP - 376
JO - American Journal of Medical Genetics Part B-neuropsychiatric Genetics
JF - American Journal of Medical Genetics Part B-neuropsychiatric Genetics
IS - 6
ER -