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. 2020 Mar;183(2):128-139.
doi: 10.1002/ajmg.b.32767. Epub 2019 Dec 19.

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder

Rachel D Reichman  1 , Sophia C Gaynor  1 , Eric T Monson  1 , Marie E Gaine  2 , Meredith G Parsons  1 , Peter P Zandi  3 , James B Potash  4 , Virginia L Willour  1
Affiliations

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder

Rachel D Reichman et al. Am J Med Genet B Neuropsychiatr Genet. 2020 Mar.

Abstract

Glutamatergic signaling is the primary excitatory neurotransmission pathway in the brain, and its relationship to neuropsychiatric disorders is of considerable interest. Our previous attempted suicide genome-wide association study, and numerous studies investigating gene expression, genetic variation, and DNA methylation have implicated aberrant glutamatergic signaling in suicide risk. The glutamatergic pathway gene LRRTM4 was an associated gene identified in our attempted suicide genome-wide association study, with association support seen primarily in females. Recent evidence has also shown that glutamatergic signaling is partly regulated by sex-related hormones. The LRRTM gene family encodes neuronal leucine-rich transmembrane proteins that localize to and promote glutamatergic synapse development. In this study, we sequenced the coding and regulatory regions of all four LRRTM gene members plus a large intronic region of LRRTM4 in 476 bipolar disorder suicide attempters and 473 bipolar disorder nonattempters. We identified two male-specific variants, one female- and five male-specific haplotypes significantly associated with attempted suicide in LRRTM4. Furthermore, variants within significant haplotypes may be brain expression quantitative trait loci for LRRTM4 and some of these variants overlap with predicted hormone response elements. Overall, these results provide supporting evidence for a sex-specific association of genetic variation in LRRTM4 with attempted suicide.

Keywords: LRRTM4; glutamatergic signaling; haplotype; sex specificity; suicidal behavior.

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Figures

FIGURE 1
FIGURE 1
Individual variants in four human LRRTM family genes. Each gene (1–4) displays the mRNA (exons are blue blocks, and introns are blue hash-marked lines) along the bottom rows, and the variants found from the fine-mapping experiments in this text are displayed as vertical tick-marks at the top of each image. The color of the variants ranges from black to light gray, depending on the significance of the variant (black is most significant). LRRTM1–3 do not have any significant variants that survived multiple correction, nor do they have any significant haplotypes. LRRTM4 has five male-specific haplotype blocks (blue horizontal bars above variants), and one female-specific haplotype block (red horizontal bar above variants). There are also red and blue vertical lines representing the male variants from this study that survived multiple correction, and the female-specific variant from the previous genome-wide association study. There are two blue variants, however their close proximity prevents them from being distinguishable at this scale
FIGURE 2
FIGURE 2
Haplotype blocks divided by sex-specificity within LRRTM4 intron 3. Both images display haplotype blocks traced to the LD map. (a) The female haplotype block contains the top female-specific variant from the previous GWAS study and the red lines outline where the haplotype falls within the LD blocks. (b) The five male haplotype blocks are displayed and red vertical lines trace to the LD block to which each haplotype is associated. Both panels display the gene track in blue and conservation in green. The AR and ER HRE tracks are the black tracks below the conservation track (green). All haplotypes are colored to indicate variant significance: The top 10 significant variants are red (p < .05), additional nominally significant variants are green, and nonsignificant variants are black. LD blocks are outlined in black over the red map at the bottom of each panel. AR, androgen receptors; ER, estrogen receptor; GWAS, genome-wide association study; HRE, hormone response element; LD, linkage disequilibrium
See this image and copyright information in PMC

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