Estimating the Genetic Variance of Major Depressive Disorder Due to All Single Nucleotide Polymorphisms

doi:10.1016/j.biopsych.2012.03.011

Biological Psychiatry

Volume 72, Issue 8, 15 October 2012, Pages 707-709

https://doi.org/10.1016/j.biopsych.2012.03.011 Get rights and content

Genome-wide association studies of psychiatric disorders have been criticized for their lack of explaining a considerable proportion of the heritability established in twin and family studies. Genome-wide association studies of major depressive disorder in particular have so far been unsuccessful in detecting genome-wide significant single nucleotide polymorphisms (SNPs). Using two recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of major depressive disorder. To assess the consistency of these two methods, we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population.

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Cited by (109)

Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank
2019, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure.
We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390).
We found significantly lower FA in the superior longitudinal fasciculus (β = −.035, p_corrected = .029) and significantly higher MD in a global measure of thalamic radiations (β = .029, p_corrected = .021), as well as higher MD in the superior (β = .034, p_corrected = .039) and inferior (β = .029, p_corrected = .043) longitudinal fasciculus and in the anterior (β = .025, p_corrected = .046) and superior (β = .027, p_corrected = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts.
Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.
Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use
2018, Drug and Alcohol Dependence
Citation Excerpt :
In addition, the aggregate effect of all SNPs included in a GWAS does not fully capture the family-based heritability of traits. For alcohol consumption and tobacco use, GWAS SNPs generally capture less than 50% of the twin-based heritability (Lubke et al., 2012; Mbarek et al., 2015; Vrieze et al., 2013). The proportion of the genetic liability which has not yet been explained by the studied common variants is referred to as “the missing heritability” (Manolio et al., 2009).
Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.
We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of “alcoholism” (N = 25,508) and “tobacco use disorder” (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.
The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10⁻⁷) and rs8034191 (p = 6.31 × 10⁻⁷) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.
Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.
TLR4 gene polymorphism associated with lifetime cigarette smoking in bipolar disorder
2017, Journal of Neuroimmunology
Citation Excerpt :
Its installation and maintenance are under the influence of several biological, psychological and social risk factors. Nicotine dependence has a strong heritable component dependent of many additive genetic risk factors with small effect sizes (Ducci and Goldman, 2012) (Belsky et al., 2013; Lubke et al., 2012). Thirty to seventy percent of patients diagnosed with bipolar disorder (BD) smoke (Lasser et al., 2000; Heffner et al., 2011).
Bipolar disorder (BD) is associated with an increased risk of tobacco dependence, the leading addictive substance worldwide. Toll-like receptor 4, a sensor of pathogens and of products of cellular stress and damage, is a major innate immune molecule and logical candidate gene for tobacco dependence in BD because (i) the involvement of TLR4 molecules in several substance use disorders has been suggested, (ii) and the association between the TLR4 gene and BD. We analysed herein the potential association between six TLR4 polymorphisms and lifetime tobacco smoking in 514 BD patients. Significant association between tobacco smoking and rs10759932 was found (genotype, Cochrane Armitage trend test, p = 0.008, p_corrected = 0.040 and alleles, p = 0.008; p_corrected = 0.040), where the C minor allele is associated with a protective effect, even after adjusting for confounding factors (OR = 1.54 [1.04–2.30], p = 0.03). Our results suggest that TLR4 gene polymorphism may act as an intermediate factor for the association between tobacco smoking addiction and BD.
Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese
2017, Gene
Citation Excerpt :
In the present study, we found seven potentially deleterious variants in the three candidate genes for MDD and SA in 36 Hong Kong Chinese patients. Two previous reports suggested that the common variants could explain the heritability of MDD only in a range from 21% to 30% (Lubke et al., 2012; Lee et al., 2013). Regarding genome-wide association (GWA) studies only captured the common variants, the missing heritability of MDD could be explained by the low-frequency and rare variants (Eichler et al., 2010; Yang et al., 2011).
To date almost 200 genes were found to be associated with major depressive disorder (MDD) or suicide attempts (SA), but very few genes were reported for their molecular mechanisms. This study aimed to find out whether there were common or rare variants in three candidate genes altering the risk for MDD and SA in Chinese.
Three candidate genes (HOMER1, SLC6A4 and TEF) were chosen for resequencing analysis and association studies as they were reported to be involved in the etiology of MDD and SA. Following that, bioinformatics analyses were applied on those variants of interest.
After resequencing analysis and alignment for the amplicons, a total of 34 common or rare variants were found in the randomly selected 36 Hong Kong Chinese patients with both MDD and SA. Among those, seven variants show potentially deleterious features. Rs60029191 and a rare variant located in regulatory region of the HOMER1 gene may affect the promoter activities through interacting with predicted transcription factors. Two missense mutations existed in the SLC6A4 coding regions were firstly reported in Hong Kong Chinese MDD and SA patients, and both of them could affect the transport efficiency of SLC6A4 to serotonin. Moreover, a common variant rs6354 located in the untranslated region of this gene may affect the expression level or exonic splicing of serotonin transporter. In addition, both of a most studied polymorphism rs738499 and a low-frequency variant in the promoter region of the TEF gene were found to be located in potential transcription factor binding sites, which may let the two variants be able to influence the promoter activities of the gene.
This study elucidated the potentially molecular mechanisms of the three candidate genes altering the risk for MDD and SA. These findings implied that not only common variants but rare variants could make contributions to the genetic susceptibility to MDD and SA in Chinese.
Orbitofrontal cortex volume links polygenic risk for smoking with tobacco use in healthy adolescents
2022, Psychological Medicine
Genetic stratification of depression by neuroticism: Revisiting a diagnostic tradition
2020, Psychological Medicine

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Techniques and MethodsEstimating the Genetic Variance of Major Depressive Disorder Due to All Single Nucleotide Polymorphisms

Am J Hum Genet

Am J Hum Genet

Schizophrenia genetics: Where next?

Schizophr Bull

Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo

Mol Psychiatry

Genome-wide association study of major depressive disorder: New results, meta-analysis, and lessons learned

Mol Psychiatry

Common SNPs explain a large proportion of the heritability for human height

Nat Genet

Uncovering the total heritability explained by all true susceptibility variants in a genome-wide association study

Genet Epidemiol

Evaluating the heritability explained by known susceptibility variants: A survey of ten complex diseases

Genet Epidemiol

The Netherlands Twin Register Biobank: A resource for genetic epidemiological studies

Twin Res Hum Genet

Techniques and Methods
Estimating the Genetic Variance of Major Depressive Disorder Due to All Single Nucleotide Polymorphisms