Najaf Amin: Rare coding genetic variation and downstream omics hold the key to understanding the pathogenesis of depression

Where were you born, and where do you live now?

I was born in Islamabad, Pakistan. After winning a scholarship in 2005 from the Higher Education Commission of Pakistan to pursue a master's degree, which led to a PhD, I moved to the Netherlands, where I completed my PhD in Genetic Epidemiology at the Department of Epidemiology, Erasmus University, Rotterdam. I continued working at the department as a postdoctoral researcher and was later appointed as a tenured assistant professor. After spending 14 years in the Netherlands, I moved to Oxford, UK, in 2019, where I was offered a senior position at the Nuffield Department of Population Health at the University of Oxford.

Could you give us a glimpse into your personal history, emphasizing the pivotal moments that first kindled your passion for science?

I have had a passion for science for as long as I can remember, but in a different field. Breaking electronic devices apart to extract the DC motor and build new machines with it was my favorite pastime as a kid. Batteries, wires, light bulbs, and motors were the toys I loved playing with. However, it was not until I entered college that I realized that I could solve intricate statistical and calculus problems. This increased my passion for studying statistics, which I pursued by pursuing my master's degree. Around 19 years of age, I was diagnosed with polycystic ovarian syndrome. My gynecologist told me that it was a ‘genetic disorder’ and related to obesity. Being very petite and knowing that none of the women in my family had this disorder, I was intrigued into learning how the genetics work. Ultimately, when I had the opportunity, I decided to pursue higher studies in genetics.

View Figure

• Download as Powerpoint
• Download Figure

Please share with us what initially piqued your interest in your favorite research or professional focus area.

By the time I graduated in 2011, genome‑wide association studies (GWAS) were at their height. Large consortium-based efforts, many of which I have contributed to, have identified hundreds of common, low-risk genetic variants for complex disorders. However, a carefully designed GWAS of major depression led by the Psychiatric Genomics Consortium failed to produce a single genome‑wide significant result. This changed my view of depression genetics: the disorder was far more complex than we had supposed, and solving its puzzle became a compelling challenge.

That turning point led me to investigate the ‘common‑disease‑rare‑variant’ hypothesis. Despite skepticism, this approach ultimately proved fruitful. The failure of the ‘common‑disease‑common‑variant' model—especially in illuminating the pathogenesis of depression—also motivated me to explore other molecular layers that are more responsive to environmental influences: epigenomics, metabolomics, and the gut microbiome.

We would like to know more about your career trajectory leading up to your most relevant leadership role. What defining moments channeled you toward that leadership responsibility?

I cannot identify a single defining moment in my career. Instead, my development has been shaped by the failures I have faced and each step I have taken—guided in large part by Professor Cornelia van Duijn (see Figure 2). I embraced opportunities as they arose.

View Figure

• Download as Powerpoint
• Download Figure

A few years into my PhD, our senior bioinformatician, who was also my immediate supervisor, left the department. At that time, the department was producing substantial genome-wide genetic data that required processing, including genotype calling, quality control, and formatting for analysis. Although I did not yet have the complete skill set, Prof. van Duijn entrusted me with that responsibility. This was both a challenge and an opportunity to bridge a critical gap in the group, and from that point, I became the lead bioinformatician.

Early in my PhD, I also took on teaching and training junior researchers. These responsibilities provided me with valuable experience in mentorship. As the group's lead analyst, I contributed to many genome‑wide association studies (GWAS) investigating complex traits/diseases of the brain, eye, lung, cardiovascular system, metabolism, and anthropometry. Working on multiple diseases with distinguished scientists around the world in large international collaborations was extraordinarily educational. Each project presented different issues and required bespoke solutions, deepening my understanding of various diseases and sharpening my epidemiological problem-solving skills.

During and after my postdoc, I enjoyed considerable freedom to pursue my research interests alongside fulfilling my departmental duties. I used this autonomy to focus on the fields I am most passionate about. In summary, my career has been built upon a combination of having a great mentor, seizing opportunities, being willing to learn and stretch beyond my comfort zone, and, above all, dedication to my work.

What is a decision or choice that seemed like a mistake at the time but ended up being valuable or transformative for your career or life?

Choosing to pursue a PhD in the Netherlands over accepting a coveted assistant director position in the civil service — a role many in my home country dream of — was a bold and uncertain decision. I arrived in the Netherlands on a modest monthly stipend, barely enough to cover the rent of a small studio apartment. I faced an unclear future and had stepped into the field of genetics with no prior knowledge or background.

By the end of my second year of my PhD, nothing seemed to be working. I lacked the foundational expertise and programming skills essential for the field. The first two projects I had invested in had stalled; I had no publications to show for my efforts and had all but lost hope. It was during this low point that I broke down emotionally in front of my mentor, Professor Cornelia van Duijn (see Figure 2). Her response was simple yet powerful — she ensured I never had to complain again. That moment marked a turning point, one that changed everything.

What habits and values did you develop during your academic studies or subsequent postdoctoral experiences that you uphold within your research environment?

Self-accountability, thinking critically, being open-minded, and last but not least, getting out of the comfort zone, without which you can never grow as a scientist.

Please tell us more about your current scholarly focal points within your chosen field of science.

Over the past twelve years, my research has focused on elucidating the rare genetic architecture and modifiable molecular pathways in major depression. During this time, I have identified several promising candidate genes and biomarkers, some of which show strong potential to lie within causal pathways.

My current work aims to experimentally verify the causal associations between genetic and environmental risk factors for major depression and their intermediate, as well as downstream, molecular consequences. In doing so, I aim to develop an integrated model that encompasses the entire chain of causation, from risk to molecular perturbation to clinical outcome.

What impact do you hope to achieve in your field by focusing on specific research topics?

Major depression is perhaps the most misunderstood among common complex diseases. While traditionally seen primarily as a disorder of the brain—affected by neurotransmitter imbalances, neural circuitry, or structural changes—recent research (including my own) makes it increasingly clear: major depression is fundamentally a systemic disease, involving multiple bodily systems, not just the central nervous system.

In particular, studies have shown that depression is associated with disturbances in the immune system, the hypothalamic-pituitary-adrenal (HPA) stress axis, oxidative stress, metabolic and gut dysfunction, and other somatic changes. These findings help explain why depression is often comorbid with chronic physical illnesses, why it affects the body's physiology, and why it contributes to higher morbidity and mortality outside of its direct psychological effects.

The goal of my research is to deepen our understanding of the multifaceted nature of depression, including its genetic, molecular, psychological, social, and environmental drivers, as well as the feedback loops among them, so that we can move beyond one-size-fits-all models. For example, mapping out causal feedback loops among biological, psychological, and social factors reveals how different drivers can reinforce each other, maintaining or worsening illness over time.

Ultimately, this richer understanding will support the development of personalized medicine in mental health: tailoring diagnosis, prevention, and treatment to the individual, considering their biological markers (such as genetic, metabolic or inflammatory profiles), their life history (early life trauma, stress exposure), clinical presentation (symptom subtypes, severity), and their social/environmental context. In this way, treatments can be more effective, remission more attainable, and health outcomes across both mental and physical domains can improve.

What do you most enjoy in your capacity as an academic or research leader?

While I enjoy most aspects of my work, interpreting results and connecting the dots to see the big picture is what I find the most rewarding.

At Genomic Press, we prioritize fostering research endeavors based solely on their inherent merit, uninfluenced by geography or the researchers' personal or demographic traits. Are there particular cultural facets within the scientific community that warrant transformative scrutiny, or is there a cause within science that you feel strongly devoted to?

The scientific community still has considerable work to do in fully embracing equality, diversity, and inclusion, particularly in the processes of awarding grants and promotions. As a brown woman from a developing country, I find that I must invest at least twice the effort of many of my European counterparts to achieve outcomes of comparable scale. Scientific merit and accomplishments alone are insufficient to advance one's career; there are numerous barriers to navigate.

Another troubling trend is the rise of “packaging culture,” which has permeated nearly every field and has now infiltrated science as well. Too often, superficial presentation is prioritized over substance. In many cases, the quality of the work and its content are overshadowed by how it is packaged or marketed.

Outside professional confines, how do you prefer to allocate your leisure moments, or conversely, in what manner would you envision spending these moments given a choice?

Spending quality time with my six-year-old son, cooking, enjoying the company of the few friends that I have, and reading articles about astronomy.

What is your most marked characteristic?¹

It is resilience and conscientiousness; as a scientist, it is the ability to see the larger picture.

Among your talents, which one(s) give(s) you a competitive edge?

The analytical mind, combined with the knowledge and experience I have gained since earning my doctorate.

If you could change one thing about yourself, what would it be?

Patience, I run out of it very quickly, especially when people are unable to be brief and concise.

What is your current state of mind?

Content in general, but anxious about the direction in which the world is moving.

What is your idea of perfect happiness?

Research without having to worry about funding.

When and where were you happiest? And why were so happy then?

I will always recall three very happy moments in my life: my graduation, the birth of my son after fourteen years of trying and experiencing several miscarriages, and finally, when the court granted me a divorce after nearly four and a half years of applying for it.

What is your greatest fear?

Leaving my son behind in a world without moral values.

What is your greatest regret?

There are no regrets, just lessons learned.

What are you most proud of?

Knowledge, skills, and what I have achieved so far despite my origin and all the trials and tribulations that I have faced in my life, and on top of all, my resilient nature.

What do you consider your greatest achievement?

Academically, the knowledge that I have gained during and after PhD. Personally, maintaining a very positive attitude despite experiencing major setbacks in life.

What or who is your greatest passion?

Searching for the truth. Exploring the unexplored.

What is your favorite occupation (or activity)

Academic research.

What is your greatest extravagance?

Luxury cars.

What is your most treasured possession?

My son.

Where would you most like to live?

In a peaceful and friendly neighborhood.

What is the quality you most admire in people?

Dignity and integrity.

What is the trait you most dislike in people?

Hypocrisy and gullibility.

What do you consider the most overrated virtue?

Selflessness to the extent that it becomes a self-sabotaging behavior.

What do you most value in your friends?

Honesty and loyalty.

Which living person do you most admire?

The two people I admire most are the two women who made me. First, my mother, Gul Shagufta, a single mother who, with limited resources, raised four children and enabled us all to achieve a high level of education. Second, Prof. Cornelia van Duijn, a top scientist whose mentorship has brought out the very best in me (see Figure 2).

Who are your heroes in real life?

Those who fight against injustice and oppression and help others in need.

If you could have dinner with any historical figure, who would it be and why?

Benazir Bhutto: She was a trailblazer in every sense. In 1988, she became the first woman to lead a Muslim‐majority country, and one of the youngest prime ministers in the world, at just 35. She came of age in a time when a repressive dictatorship had suppressed democratic institutions and gutted civil liberties. Her father, Zulfikar Ali Bhutto, was overthrown and later executed. Despite this, she rose to become a symbol of resistance against authoritarianism. Pro-democracy, pro-education, pro-freedom, and pro-social welfare, her policies were a breath of fresh air to the country after 11 long years of oppression and dictatorship.

She also faced enormous opposition, including from entrenched military interests, political rivals, a culture that questioned women's public leadership, and institutions resistant to reform. Nonetheless, she persisted. Her strength, courage, and foresight were unmatched. Being a zealous teenager madly in love with her charismatic personality, I met her several times during my college days, but I never had the opportunity to talk to her.

Who are your favorite writers?

Lord Francis Bacon, mainly because of his style of writing, which is concise and aphoristic.

Who are your heroes of fiction?

Frankenstein.

What aphorism or motto best encapsulates your life philosophy?

“Failure is delay, not defeat. It is a temporary detour, not a dead end.”

—Denis Waitley, American motivational speaker and author