Friday, June 17, 2016

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism

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Hansen T, Hartman CA, Haworth CM, Hayward C, Heath AC, Hinds DA, Hyppönen E,
Iacono WG, Järvelin MR, Jöckel KH, Kaprio J, Kardia SL, Keltikangas-Järvinen L,
Kraft P, Kubzansky LD, Lehtimäki T, Magnusson PK, Martin NG, McGue M, Metspalu A,
Mills M, de Mutsert R, Oldehinkel AJ, Pasterkamp G, Pedersen NL, Plomin R,
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Laibson DI, Medland SE, Meyer MN, Pickrell JK, Esko T, Krueger RF, Beauchamp JP,
Koellinger PD, Benjamin DJ, Bartels M, Cesarini D. Genetic variants associated
with subjective well-being, depressive symptoms, and neuroticism identified
through genome-wide analyses. Nat Genet. 2016 Jun;48(6):624-33.

Abstract

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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From the article
Subjective well-being—as measured by survey questions on life satisfaction, positive affect, or happiness—is a major topic of research in psychology, economics, and epidemiology. Twin studies have found that subjective well-being is genetically correlated with depression (characterized by negative affect, anxiety, low energy, bodily aches and pains, pessimism, and other symptoms) and neuroticism (a personality trait characterized by easily experiencing negative emotions such as anxiety and fear). Depression and neuroticism have received much more attention than subjective well-being in genetic association studies, but the discovery of genetic variants associated with either of them has proven elusive.
Here we report a series of separate and joint analyses of subjective well-being, depressive symptoms, and neuroticism, which identify 16 genome-wide significant associations across the three phenotypes. In our two joint analyses, we exploit the high genetic correlation between subjective well-being, depressive symptoms, and neuroticism (i) to evaluate the credibility of the associations from our initial genome-wide association study (GWAS) and (ii) to identify new associations (beyond those identified by the GWAS)...
We found significant enrichment of central nervous system for all three phenotypes and, perhaps more surprisingly, enrichment of adrenal/pancreas for subjective well-being and depressive symptoms. The cause of the adrenal/pancreas enrichment is unclear, but we note that the adrenal glands produce several hormones, including cortisol, epinephrine, and norepinephrine, known to have important roles in the bodily regulation of mood and stress. It has been robustly found that blood serum levels of cortisol in patients afflicted by depression are elevated relative to those in controls.

3 comments:

  1. Genetics of Personality Consortium, de Moor MH, van den Berg SM, Verweij KJ,Krueger RF, Luciano M, Arias Vasquez A, Matteson LK, Derringer J, Esko T, Amin N, Gordon SD, Hansell NK, Hart AB, Seppälä I, Huffman JE, Konte B, Lahti J, Lee M, Miller M, Nutile T, Tanaka T, Teumer A, Viktorin A, Wedenoja J, Abecasis GR, Adkins DE, Agrawal A, Allik J, Appel K, Bigdeli TB, Busonero F, Campbell H, Costa PT, Davey Smith G, Davies G, de Wit H, Ding J, Engelhardt BE, Eriksson JG, Fedko IO, Ferrucci L, Franke B, Giegling I, Grucza R, Hartmann AM, Heath AC, Heinonen K, Henders AK, Homuth G, Hottenga JJ, Iacono WG, Janzing J, Jokela M, Karlsson R, Kemp JP, Kirkpatrick MG, Latvala A, Lehtimäki T, Liewald DC, Madden PA, Magri C, Magnusson PK, Marten J, Maschio A, Medland SE, Mihailov E, Milaneschi Y, Montgomery GW, Nauck M, Ouwens KG, Palotie A, Pettersson E, Polasek O, Qian Y, Pulkki-Råback L, Raitakari OT, Realo A, Rose RJ, Ruggiero D, Schmidt CO, Slutske WS, Sorice R, Starr JM, St Pourcain B, Sutin AR, Timpson NJ, Trochet H, Vermeulen S, Vuoksimaa E, Widen E, Wouda J, Wright MJ, Zgaga L, Porteous D, Minelli A, Palmer AA, Rujescu D, Ciullo M, Hayward C, Rudan I, Metspalu A, Kaprio J, Deary IJ, Räikkönen K, Wilson JF, Keltikangas-Järvinen L, Bierut LJ, Hettema JM, Grabe HJ, van Duijn CM, Evans DM, Schlessinger D, Pedersen NL, Terracciano A, McGue M, Penninx BW, Martin NG, Boomsma DI. Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive
    Disorder. JAMA Psychiatry. 2015 Jul;72(7):642-50. (Continued)

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  2. (continued)
    Abstract
    IMPORTANCE:
    Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases).
    OBJECTIVES:
    To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD.
    DESIGN, SETTING, AND PARTICIPANTS:
    Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014.
    MAIN OUTCOMES AND MEASURES:
    Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.
    RESULTS:
    A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P < .05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts.
    CONCLUSIONS AND RELEVANCE:
    This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

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  3. Ware EB, Mukherjee B, Sun YV, Diez-Roux AV, Kardia SL, Smith JA. Comparative genome-wide association studies of a depressive symptom phenotype in a repeated measures setting by race/ethnicity in the Multi-Ethnic Study of Atherosclerosis. BMC Genet. 2015 Oct 12;16:118.

    Abstract
    BACKGROUND:
    Time-varying phenotypes have been studied less frequently in the context of genome-wide analyses across ethnicities, particularly for mood disorders. This study uses genome-wide association studies of depressive symptoms in a longitudinal framework and across multiple ethnicities to find common variants for depressive symptoms. Ethnicity-specific GWAS for depressive symptoms were conducted using three approaches: a baseline measure, longitudinal measures averaged over time, and a repeated measures analysis. We then used meta-analysis to jointly analyze the results across ethnicities within the Multi-ethnic Study of Atherosclerosis (MESA, n = 6,335), and then within ethnicity, across MESA and a sample from the Health and Retirement Study African- and European-Americans (HRS, n = 10,163).
    METHODS:
    This study uses genome-wide association studies of depressive symptoms in a longitudinal framework and across multiple ethnicities to find common variants for depressive symptoms. Ethnicity-specific GWAS for depressive symptoms were conducted using three approaches: a baseline measure, longitudinal measures averaged over time, and a repeated measures analysis. We then used meta-analysis to jointly analyze the results across ethnicities within the Multi-ethnic Study of Atherosclerosis (MESA, n = 6,335), and then within ethnicity, across MESA and a sample from the Health and Retirement Study African- and European-Americans (HRS, n = 10,163).
    RESULTS:
    Several novel variants were identified at the genome-wide suggestive level (5×10(-8) < p-value ≤ 5×10(-6)) in each ethnicity for each approach to analyzing depressive symptoms. The repeated measures analyses resulted in typically smaller p-values and an increase in the number of single-nucleotide polymorphisms (SNP) reaching genome-wide suggestive level.

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