Genetics Alone Not Enough to Predict Early-Onset Depression

Batya Swift Yasgur, MA, LSW

January 20, 2021

Genomic risk scores can help predict early-onset depression, but only in conjunction with other factors, new research suggests.

Investigators found that polygenic risk score (PRS) had no edge over other risk factors in predicting early-onset depression but that it was useful in identifying depression risk in conjunction with parental psychiatric history and socioeconomic status (SES).

"Both polygenic and family factors are associated with a child's long-term risk of developing severe depression," lead author Esben Agerbo, DrMedSc, professor, Lundbeck Foundation for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark, told Medscape Medical News.

"Given our current understanding, we cannot say genetic factors are more predictive of depression, but they are a great addition to usual factors," said Agerbo, who is also a professor at the School of Business and Social Sciences.

The study was published online January 13 in JAMA Psychiatry.

Genetic "Hype"

PRS is a predictive measure based on the concept that underlying susceptibility to major depression is "polygenic," meaning that the heritable component is "distributed across numerous genetic variants," the authors note.

"Estimates of the genome-wide single-nucleotide polymorphism–based hereditability...range from approximately 8% to 32%, depending on phenotype definition, and PRSs (a weighted sum of total polygenic burden) explain approximately 1.9% of the variance," they add.

On the other hand, increasing evidence points to parental history of depression or of other severe mental disorders as being associated with childhood depression, and epidemiologic research has found that parental SES during the child's upbringing is likewise associated with risk for major depression.

The "impact of these risk factors may partly be mediated by the offspring's genetic predisposition to depression," the researchers note.

Few studies have attempted to quantify the "interplay between parental risk factors and the genetic liability of depression," and few studies have examined PRSs for depression together with epidemiologic factors, they add.

"Often, there is a lot of hype around genetics, and the importance of genetics is overevaluated, [which] is not only true in depression; and here, I wanted to compare the impact of genetics alongside other risk factors," Agerbo said.

"Genetics is, in many ways, exactly like any other risk factors — a high genetic liability does not mean that one is doomed, it merely increases the risk," he continued.

To investigate the interplay between PRSs for depression and parental psychiatric history and SES, the researchers turned to iPSYCH, a large Danish population-based case cohort sample of singletons born from May 1, 1981, to December 31, 2005 (n = 88,764).

The researchers used these data in conjunction with information about mental diseases as well as socioeconomic data, both drawn from large Danish population-wide databases.

The PRSs were derived from genome-wide association study summary statistics, which encompassed 44 genetic risk variants for major depression.

The researchers analyzed variables for SES (eg, education, employment, and marital status) recorded in the year of the participants' tenth birthdays, as well as whether parents had a psychiatric condition before their offspring's tenth birthday. Psychiatric disorders were classified either as major depression, bipolar or psychotic disorders, or other mental disorders.

PRS Variables

The final sample consisted of 17,098 patients with depression and 18,583 individuals drawn at random from the base population (68.7% and 49.3% were female, respectively). The random sample of those from the Danish population included 362 individuals with depression.

Women were twice as likely to be diagnosed with depression as men (hazard ratio [HR], 2.25; 95% CI, 2.14 – 2.36). The hazard that increased by 31% per 1-SD increase in the PRS (95% CI, 1.28 – 1.34).

PRS, parental history, and lower SES were all significantly associated with the risk for depression.

Characteristic Crude HR (95% CI)
PRS (per 100-SD increase in score) 1.31 (1.28 – 1.34)
Maternal psychiatric history (major depression) 2.25 (1.87 – 2.71)
Maternal psychiatric history (bipolar, mood, psychotic disorder) 2.25 (1.70 – 2.97)
Paternal psychiatric history (major depression) 2.13 (1.68 – 2.69)
Paternal psychiatric history (bipolar, mood, psychotic disorder 1.89 (1.44 – 2.49)
Maternal educational attainment (primary school) 1.65 (1.45 – 1.87)
Maternal educational attainment (high school/vocational training) 1.29 (1.14 – 1.45)
Parental unemployment 1.75 (1.61 – 1.89)

"Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another," the authors write.

On the other hand, the absolute risk for depression by age 30 years "differed substantially," depending on the individual's combination of risk factors, the authors report.

For example, those with the lowest absolute risk were men with high SES who were in the bottom 2% of the PRS distribution. By contrast, women in the top 2% of the PRS distribution, who had a parental history of psychiatric disorders, were at the highest risk (1.0%; 95% CI,1% – 2.0%; vs 23.7%; 95% CI, 16.6% – 30.2%).

"Work on the development of approaches for preventing depression in high-risk groups must proceed in tandem with the development of PRS variables themselves for their inclusion in clinical practice to be beneficial," the investigators note.

Toward More Accurate Prediction

Commenting on the study for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, Toronto, Canada, said the study shows that "environmental determinants multiplied by genetics equals depression — something we've known for decades."

We need to "have better understanding of which genetics interact with which environmental factors to increase the risk of depression.... PRS gives us a quantitative composite of the genetics and is more instructive than just looking at genetics alone," said McIntyre, who is also the chairman and executive director of the Brain and Cognition Discovery Foundation, Toronto. He was not involved with the study.

"The take-away message is that we need to have better characterization of PRS with the event to prognosticate depression," he added.

The study was supported by grants from the Lundbeck Foundation (iPSYCH) and the Stanley Medical Research Institute. Individual researchers were supported by grants from the Lundbeck Foundation, the Danish National Research Foundation, the Queensland Center for Mental Health Research, and the European Union's Horizon 2020 Research and Innovation Programme. Agerbo reports no relevant financial relationships. The other authors' disclosures are listed on the original article. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and Abbvie. McIntyre is also CEO of AltMed.

JAMA Psychiatry. Published online January 13, 2021. Abstract

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