Genetic Risk For Major Depression Research Articles

The joint effects of genetic liability and the death of close relatives on risk for major depression and alcohol use disorder in a Swedish national sample.

To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor - death of spouse, parent, and sibling - in predicting episodes of, respectively, MD and AUD. MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960-1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event - a registration for MD within 6 months or AUD within a year - on an additive scale, using the Nelson-Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS). In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD. Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD.

Genetic risk for chronic pain is associated with lower antidepressant effectiveness: Converging evidence for a depression subtype.

Chronic pain and depression are highly comorbid and difficult-to-treat disorders. We previously showed this comorbidity is associated with higher depression severity, lower antidepressant treatment effectiveness and poorer prognosis in the Australian Genetics of Depression Study. The current study aimed to assess whether a genetic liability to chronic pain is associated with antidepressant effectiveness over and above the effect of genetic factors for depression in a sample of 12,863 Australian Genetics of Depression Study participants. Polygenic risk scores were calculated using summary statistics from genome-wide association studies of multisite chronic pain and major depression. Cumulative linked regressions were employed to assess the association between polygenic risk scores and antidepressant treatment effectiveness across 10 different medications. Mixed-effects logistic regressions showed that individual genetic propensity for chronic pain, but not major depression, was significantly associated with patient-reported chronic pain (PainPRS OR = 1.17 [1.12, 1.22]; MDPRS OR = 1.01 [0.98, 1.06]). Significant associations were also found between lower antidepressant effectiveness and genetic risk for chronic pain or for major depression. However, a fully adjusted model showed the effect of PainPRS (adjOR = 0.93 [0.90, 0.96]) was independent of MDPRS (adjOR = 0.96 [0.93, 0.99]). Sensitivity analyses were performed to assess the robustness of these results. After adjusting for depression severity measures (i.e. age of onset; number of depressive episodes; interval between age at study participation and at depression onset), the associations between PainPRS and patient-reported chronic pain with lower antidepressant effectiveness remained significant (0.95 [0.92, 0.98] and 0.84 [0.78, 0.90], respectively). These results suggest genetic risk for chronic pain accounted for poorer antidepressant effectiveness, independent of the genetic risk for major depression. Our results, along with independent converging evidence from other studies, point towards a difficult-to-treat depression subtype characterised by comorbid chronic pain. This finding warrants further investigation into the implications for biologically based nosology frameworks in pain medicine and psychiatry.

The patterns of family genetic risk scores for eleven major psychiatric and substance use disorders in a Swedish national sample

To clarify the structure of genetic risks for 11 major psychiatric disorders, we calculated, from morbidity risks for disorders in 1st–5th degree relatives controlling for cohabitation effects, in the Swedish population born between 1932 and 1995 (n = 5,830,014), the family genetic risk scores (FGRS) for major depression (MD), anxiety disorders (AD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), bulimia (BUL), anorexia nervosa (AN), alcohol use disorder (AUD), drug use disorder (DUD), ADHD, and autism-spectrum disorder (ASD). For all affected individuals, we calculated their mean standardized FGRS for each disorder. The patterns of FGRS were quite similar for MD and AD, and for AUD and DUD, but substantially less similar for BUL and AN, BD and SZ, and ADHD and ASD. While OCD had high levels of FGRS for MD and AD, the overall FGRS profile differed considerably from MD and AD. ADHD FGRS scores were substantially elevated in AUD and DUD. FGRS scores for BD, OCD, AN, ASD, ADHD, and especially SZ were relatively disorder-specific while genetic risk for MD and AD had more generalized effects. The levels of FGRS for BMI, coronary artery disease, and educational attainment across our disorders replicated prior associations found using molecular genetic methods. All diagnostic categories examined had elevated FGRS for many disorders producing, for each condition, an informative FGRS profile. Using a novel method which approximates, from pedigree data, aggregate genetic risk, we have replicated and extended prior insights into the structure of genetic risk factors for key psychiatric illnesses.

Polygenic Risk for Major Depression Interacts with Parental Criticism in Predicting Adolescent Depressive Symptom Development

Research has focused more and more on the interplay between genetics and environment in predicting different forms of psychopathology, including depressive symptoms. While the polygenic nature of depressive symptoms is increasingly recognized, only few studies have applied a polygenic approach in gene-by-environment interaction (G × E) studies. Furthermore, longitudinal G × E studies on developmental psychopathological properties of depression are scarce. Therefore, this 6-year longitudinal community study examined the interaction between genetic risk for major depression and a multi-informant longitudinal index of critical parenting in relation to depressive symptom development from early to late adolescence. The sample consisted of 327 Dutch adolescents of European descent (56% boys; Mage T1 = 13.00, SDage T1 = 0.44). Polygenic risk for major depression was based on the Hyde et al. (Nature Genetics, 48, 1031–1036, 2016) meta-analysis and genetic sensitivity analyses were based on the 23andMe discovery dataset. Latent Growth Models suggested that polygenic risk score for major depression was associated with higher depressive symptoms across adolescence (significant main effect), particularly for those experiencing elevated levels of critical parenting (significant G × E). These findings highlight how polygenic risk for major depression in combination with a general environmental factor impacts depressive symptom development from early to late adolescence.

The Genetic Epidemiology of Treated Major Depression in Sweden

The authors examined the heritability of treated major depression in a twin and full/half-sibling design, to describe key genetic epidemiological features of major depression and to determine which clinical indices of genetic liability optimally predict risk of depression in relatives. The authors examined all treated cases of major depression in Sweden recorded in inpatient, specialist, and primary care registries and, using OpenMx, estimated the etiologic role of genetic and environmental factors from monozygotic and dizygotic twin pairs and full and half siblings reared together and apart (total N=1,718,863 pairs). Eight indices of genetic risk were examined in 875,010 proband-relative pairs. The heritability of major depression in men and women was estimated at 0.41 (95% CI=0.21, 0.49) and 0.49 (95% CI=0.31, 0.56), respectively, in the twin design and 0.36 (95% CI=0.31, 0.38) and 0.51 (95% CI=0.51, 0.53), respectively, in the independent full/half-sibling design. The best estimate of the correlation in genetic effects across sexes was 0.89 (95% CI=0.87, 0.91). The results also showed evidence of modest shared environmental effects (0.02-0.05). Seven of the eight indices predicted risk for major depression in relatives, with stronger effects in those more closely related. The strongest indices were early age at onset, recurrence, comorbid anxiety disorder, and measures of clinical severity. In a large national sample, the heritability of major depression was similar when estimated from twin and full/half-sibling designs. The heritability of major depression was greater in women than in men, with the two sexes sharing most but not all genetic risk factors. In affected individuals, genetic risk for major depression could be meaningfully assessed from commonly available clinical indices.

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association (GWA) meta-analysis based in 135,458 cases and 344,901 control, We identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression, and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relations of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine and define the basis of major depression and imply a continuous measure of risk underlies the clinical phenotype.

Robust symptom networks in recurrent major depression across different levels of genetic and environmental risk

BackgroundGenetic risk and environmental adversity—both important risk factors for major depression (MD)—are thought to differentially impact on depressive symptom types and associations. Does heterogeneity in these risk factors result in different depressive symptom networks in patients with MD? MethodsA clinical sample of 5784 Han Chinese women with recurrent MD were interviewed about their depressive symptoms during their lifetime worst episode of MD. The cases were classified into subgroups based on their genetic risk for MD (family history, polygenic risk score, early age at onset) and severe adversity (childhood sexual abuse, stressful life events). Differences in MD symptom network structure were statistically examined for these subgroups using permutation-based network comparison tests. ResultsAlthough significant differences in symptom endorsement rates were seen in 18.8% of group comparisons, associations between depressive symptoms were similar across the different subgroups of genetic and environmental risk. Network comparison tests showed no significant differences in network strength, structure, or specific edges (P-value > 0.05) and correlations between edges were strong (0.60–0.71). LimitationsThis study analyzed depressive symptoms retrospectively reported by severely depressed women using novel statistical methods. Future studies are warranted to investigate whether similar findings hold in prospective longitudinal data, less severely depressed patients, and men. ConclusionsSimilar depressive symptom networks for MD patients with a higher or lower genetic or environmental risk suggest that differences in these etiological influences may produce similar symptom networks downstream for severely depressed women.

Blue Genes? Understanding and Mitigating Negative Consequences of Personalized Information about Genetic Risk for Depression.

Personalized genetic testing for vulnerability to mental disorders is expected to become increasingly common. It is therefore important to understand whether learning about one's genetic risk for a mental disorder has negative clinical implications, and if so, how these might be counteracted. Among participants with depressive symptoms, we administered a sham biochemical test purportedly revealing participants' level of genetic risk for major depression. Participants told that they carried a genetic predisposition to depression expressed significantly lower confidence in their ability to cope with depressive symptoms than participants told they did not carry this predisposition. A short intervention providing education about the non-deterministic nature of genes' effects on depression fully mitigated this negative effect, however. Given the clinical importance of patient expectancies in depression, the notion that pessimism about one's ability to overcome symptoms could be exacerbated by genetic information-which will likely become ever more widely available-represents cause for concern. Education and counseling about the malleability of genetic effects may be an important tool for counteracting clinically deleterious beliefs that can be evoked by genetic test results. Genetic counselors may be able to help patients avoid becoming demoralized by learning they have a genetic predisposition to depression by providing education about the non-deterministic role of biology in depression, and a brief audiovisual intervention appears to be an effective approach to delivering such education.

Age of onset and family history as indicators of polygenic risk for major depression.

The extent to which earlier age of onset (AO) is a reflection of increased genetic risk for major depression (MD) is still unknown. Previous biometrical research has provided mixed empirical evidence for the genetic overlap of AO with MD. If AO is demonstrated to be relevant to molecular polygenic risk for MD, incorporation of AO as a phenotype could enhance future genetic studies. This research estimated the SNP-based heritability of AO in the China, Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) case-control sample (N = 9,854; MD case, n = 4,927). Common single nucleotide polymorphism heritability of MD was also examined across both high and low median-split AO groups, and best linear unbiased predictor (BLUP) scores of polygenic risk, in split-halves, were used to predict AO. Distributions of genetic risk across early and late AO were compared, and presence of self-reported family history (FH) of MD was also examined as a predictor of AO. AO was not significantly heritable and polygenic risk derived from the aggregated effects of common genetic variants did not significantly predict AO in any analysis. AO was modestly but significantly lower in cases with a first-degree genetic FH of MD. Findings indicate that AO is associated with greater self-reported genetic risk for MD in cases, yet not associated with common variant polygenic risk for MD. Future studies of early MD may benefit more from the examination of important moderating variables such as early life events.

Decreased regional homogeneity in insula and cerebellum: A resting-state fMRI study in patients with major depression and subjects at high risk for major depression

Functional disconnectivity during the resting state has been observed in subjects with major depressive disorder (MDD), and in subjects at high genetic risk for major depression during task performance. It is hypothesized that functional impairments in certain brain areas are present in patients with MDD and in their first-degree relatives. To test this hypothesis, an analysis of regional homogeneity (ReHo) of the whole brain was performed on 45 subjects. Compared with the control group, subjects with MDD and those at high risk for MDD exhibited significantly decreased ReHo in the right insula and in the left cerebellum. These abnormalities may play an important role in the pathophysiology of depression.

Overview: A Rare Opportunity or Just One Less Reason to Be Depressed

Overview: A Rare Opportunity or Just One Less Reason to Be Depressed

Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes?

Although women are at consistently greater risk for major depression (MD) than men, it is unclear whether sex modifies the aetiological impact of genetic factors on MD. Is the heritability of MD different in men and women? Do the same genetic risk factors predispose to MD in the two sexes? We obtained a lifetime history of MD by personal interview on two occasions from 6672 individual twins and 2974 complete twin pairs. Three diagnostic criteria of increasing narrowness were employed: DSM-III-R, DSM-III-R plus impairment and Washington University. To increase power by controlling for unreliability of assessment, we evaluated sex differences on genetic risk for MD using a structural equation measurement model. Using DSM-III-R criteria, but not the two narrower definitions, heritability of MD was significantly greater in women than in men. In the three diagnostic systems, the genetic correlation in liability to MD in men and women was estimated at between +0.50 and +0.65. These estimates differed significantly from unity for the two broader definitions. Using broad but not narrower definitions of illness, genetic factors play a greater role in the aetiology of MD in women than in men. The genes that influence risk for MD in the two sexes are correlated but are probably not entirely the same. These results raise the possibility that, in linkage and association studies, the impact of some loci on risk for MD will differ in men and women.