Genome-wide linkage scan of major depressive disorder in two Dagestan genetic isolates

Abstract

<jats:title>Abstract</jats:title><jats:p>We conducted a 10-cM genome-wide linkage scan in two extended pedigrees, ascertained from two diverse Dagestan genetic isolates with high aggregation of major depressive disorder (MDD) and suicides. Using genome wide multipoint parametric linkage analyses with short tandem repeat markers, we found two previously undetected genomic regions with significant linkage in isolate #6007 with LODs=3.1–3.4 at 2p13.2–p11.2 (and some signal in same region for #6008) and in 14q31.12–q32.13. We also obtained suggestive evidence for linkage with MDD at 9q33.3–q34.2 (#6008), 13q31.1–q31.2(#6007), 11p15(#6008), 17q25.3(#6007) and 19q13.31–q13.33 (#6008). Five regions (1p36.1–p35.2, 2p13.2–p11.2, 17q25.3, 18q22 and 22q12.3) demonstrated at least nominal linkage in both isolates’ pedigrees, while all other linkage regions demonstrated population-specific genetic heterogeneity.</jats:p>

Genomic structural variants are linked with intellectual disability

“…Three genomic regions we found linked to ID: 11q23, 12q24.23-q24.32 and 22q12.3-q13.1, have previously been reported to be associated with SCZ and MDD (Bulayeva et al, 2007; 2011; 2012). The genomic regions linked to this spectrum of clinical phenotypes were also confirmed by MRI findings in SCZ (Simic et al 1997).…”

Extensive genome-wide autozygosity in the population isolates of Daghestan

“…30,[32][33][34][68][69][70][71][72][73][74] Several genetic studies of quantitative, disease-related phenotypes have already been successfully carried out in Daghestanian small isolated communities. 30,[32][33][34][69][70][71][72][73][74] These studies observed notable within-and between-isolate diversity in clinical and genetic heterogeneity likely because of differences in founders, subsequent endogamy and inbreeding within the isolates. The results from these studies suggest that mapping genes of complex diseases, including major depressive disorder, schizophrenia, hearing loss across genetically homogeneous isolates, can facilitate detecting linkage signals and expedite the search for susceptibility genes when combined with the methods that identify structural genomic and nucleotide variation in linkage regions.…”

Co‐shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome

“…However, as described above, PRL /6p22.3, PRLR /5p13.2, PRLHR/ 10q26.13, OXT / 20p13, OXTR /3p25, and NPY /7p15.1 genes/loci have all been variably linked and/or associated with prediabetes traits, SCZ, bipolar disorder, MDD, postpartum depression, T2D, C‐reactive protein, T2D‐atherogenic particles, MetS, and CAD (An et al, ; Bespalova et al, ; Bosse et al, ; Bowden et al, ; Breen et al, ; K. Bulayeva et al, ; Divers et al, ; Fallin et al, ; Fanous et al, ; Ghosh et al, ; Gornick et al, ; Jonas et al, ; Kong et al, ; Lakka et al, ; Lu et al, ; Marcheco‐Teruel et al, ; Maziade et al, ; Montag et al, ; Myers et al, ; Nilsson et al, ; Rybakowski et al, ; Smith et al, ; Teltsh et al, ; Teltsh et al, ; Voight et al, ; Y. Wang et al, ; Wiltshire et al, ; Zeggini et al, ; Zintzaras & Ioannidis, ). Furthermore, the PRL , PRLR , PRLHR , OXT , OXTR , and NPY genes play a key role in the PRL‐pathway and may, if impaired, confer risk for T2D, Mets, associated traits, and the SCZ‐T2D and/or ‐MetS comorbidity.…”

“…OXT lies on 20p13, a locus linked and/or associated with small atherogenic LDL‐particles, large VLDL‐particles in diabetic subjects (Divers et al, ), T2D (Ghosh et al, ), MDD (K. Bulayeva et al, ), and SCZ (Fanous et al, ; Teltsh et al, ; Teltsh et al, ). OXT is not associated with childhood depression (Strauss et al, ) and is associated with postpartum depression (Jonas et al, ) and SCZ (Montag et al, ; Teltsh et al, ).…”