New Molecules in Mood Disorders, 2004-2009(NewMood)
(KTIA_13_NAP-A-II/14)
Hungarian National Brain Research Program(KTIA NAP 2017-1.2.1-NKP-2017-00002)
Nemzeti Agykutatási Program KTIA_Nap_13-1-2013-0001
Hungarian Brain Research Program(KTIA_NAP_13-2-2015-0001)
(2019-2.1.7-ERA-NET-2020-00005) Támogató: Nemzeti Kutatási, Fejlesztési és Innovációs
Hivatal
ERA PerMed(ERAPERMED2019-108)
(UNKP-17-4-I-SE-8)
(UNKP-19- 4-BME-344)
(UNKP-20-3-II-SE-51)
(UNKP-20-5-BME-92)
(UNKP- 21-5-BME-362)
(UNKP-21-4-I-SE-15)
(the Neurology and Translational Biotechnology thematic programmes of the Semmelweis
University)
(OTKA 119866)
(János Bolyai Research Scholarship)
(2020-4.1.1.-TKP2020)
(BME NC TKP2020)
(BMEIE-BIO TKP2020)
The largest migraine genome-wide association study identified 38 candidate loci. In
this study we assessed whether these results replicate on a gene level in our European
cohort and whether effects are altered by lifetime depression. We tested SNPs of the
loci and their vicinity with or without interaction with depression in regression
models. Advanced analysis methods such as Bayesian relevance analysis and a neural
network based classifier were used to confirm findings. Main effects were found for
rs2455107 of PRDM16 (OR = 1.304, p = 0.007) and five intergenic polymorphisms in 1p31.1
region: two of them showed risk effect (OR = 1.277, p = 0.003 for both rs11209657
and rs6686879), while the other three variants were protective factors (OR = 0.4956,
p = 0.006 for both rs12090642 and rs72948266; OR = 0.4756, p = 0.005 for rs77864828).
Additionally, 26 polymorphisms within ADGRL2, 2 in REST, 1 in HPSE2 and 33 mostly
intergenic SNPs from 1p31.1 showed interaction effects. Among clumped results representing
these significant regions, only rs11163394 of ADGRL2 showed a protective effect (OR
= 0.607, p = 0.002), all other variants were risk factors (rs1043215 of REST with
the strongest effect: OR = 6.596, p = 0.003). Bayesian relevance analysis confirmed
the relevance of intergenic rs6660757 and rs12128399 (p31.1), rs1043215 (REST), rs1889974
(HPSE2) and rs11163394 (ADGRL2) from depression interaction results, and the moderate
relevance of rs77864828 and rs2455107 of PRDM16 from main effect analysis. Both main
and interaction effect SNPs could enhance predictive power with the neural network
based classifier. In summary, we replicated p31.1, PRDM16, REST, HPSE2 and ADGRL2
genes with classic genetic and advanced analysis methods. While the p31.1 region and
PRDM16 are worthy of further investigations in migraine in general, REST, HPSE2 and
ADGRL2 may be prime candidates behind migraine pathophysiology in patients with comorbid
depression.
