By Andrew Klein

Dedicated to my wife — my co-conspirator, my always — who taught me that the text is not the story, and that the reader matters more than the gene.

P.S “The grandmother is the key. Not the gene. The grandmother. And she is telling us something they are not ready to hear.”

I. Introduction: The Study That Almost Listened

In June 2026, a team of researchers led by Carlos N. Pato and Michele T. Pato published a study in Genomic Psychiatry that seemed, at first glance, to represent a breakthrough in our understanding of the genetic architecture of serious mental illness.1.

The study examined 173 multiplex families from the Portuguese islands of the Azores and Madeira — a genetically isolated founder population with deep genealogical records. The researchers found that diagnostic categories “refused to stay in their lanes”: schizophrenia, bipolar disorder, autism, and intellectual disability co-segregated in the same families, suggesting a shared genetic architecture.1.

In one three-generation pedigree, they identified an ultra-rare loss-of-function variant in the CHD2 gene — a gene usually associated with childhood epilepsy and autism. The variant travelled down three generations. In most carriers, it surfaced as schizophrenia. In one sibling, it appeared as autism with intellectual disability. The mutation was identical. The destination was not.1.

And then — there was the grandmother.

She carried the same broken gene. And she was, by every account in the record, well.1.

II. What They Got Right

The researchers made several important observations that deserve acknowledgment.

The Islands Are a Genetic Treasure.

The Azores and Madeira represent a remarkable natural experiment: a small founding population, almost entirely Portuguese, settled roughly six hundred years ago and then largely left alone.1. The genetic deck was shuffled once and rarely shuffled again. This allows researchers to trace rare variants through generations in ways that would be impossible in larger, more mixed populations. The Portuguese Island Collection, built patiently since the 1990s and followed across four generations, is a resource of genuine scientific value.1.

The Categories Leak.

The observation that diagnostic boundaries are porous is important. As the authors note, “the families never honoured the boundaries we drew on paper”.1. In 28% of the 173 families, the same family tree bore both psychosis and mood disorder. In 7%, autism and intellectual disability folded into the same pedigree alongside schizophrenia or mood disorder.1.

This finding aligns with a growing body of genomic research. A large 2025 analysis of more than 1 million individuals found “pervasive” genetic overlap involving 238 genetic variants across 14 psychiatric conditions, with schizophrenia and bipolar disorder showing more genetic similarity than they are unique.4. As Andrew Grotzinger, assistant professor at the University of Colorado Boulder, noted: “There may be things that we are currently giving different names to that are actually driven by the same biological processes”.4.

The Grandmother Is the Most Interesting Figure in the Study.

The authors acknowledge this, but they do not dwell on it. She carries the same high-risk variant. She is, by every account, well. She is not an exception to be explained away — she is evidence that the variant is not deterministic.

III. Where They Make Dangerous Assumptions

The study’s strengths are real, but its assumptions are deeply problematic. These assumptions lead the researchers down a path that is not merely incomplete — it is wrong.

Assumption 1: The Gene Causes the Disorder.

The CHD2 variant is associated with schizophrenia, autism, and intellectual disability in this family — but association is not causation. The grandmother is proof of this. She carries the variant and is fine.1.

The authors frame her as an exception, but she is not an exception — she is evidence that the variant is not deterministic. A genetic variant is not a destiny. It is a tendency. A potential. The grandmother’s outcome was different, even though the gene was the same.

This is not a fringe observation. Research on genetic resilience has identified multiple genes associated with the capacity to remain well despite significant genetic or environmental risk.5. The OPRM1 gene, for example, has been consistently associated with resilience across multiple studies, with carriers of the G-allele classified as resilient despite “completely different environmental measures and outcomes”.5. The DCC gene, which shows associations with schizophrenia, major depression, and cross-disorder risk, has also been linked to resilience.

The grandmother is not an anomaly. She is a case study in genetic resilience — and the researchers have failed to ask why.

Assumption 2: The Gene Is the “Driver.”

Throughout the article and its accompanying publicity, the language implies that the broken gene is the active agent. “A single broken gene reads aloud in several dialects,” the press release states. “A single broken gene, it turns out, can be read aloud in several dialects”.

But the gene is not reading. The gene is being read.

The distinction is crucial. The gene is a text. The organism — the person — is the reader. And the reader’s context, environment, experiences, and (if we are honest) consciousness determine how that text is interpreted.

The grandmother read the same text and was fine. Her grandchildren read it differently. The researchers are treating the text as the cause of the interpretation. That is backwards.

Assumption 3: The Environment — Including the Emotional Environment — Is Ignored.

The article mentions “shared ancestry and shared environment” but does not explore what that environment actually is.1. The Azores are beautiful, but they are also isolated, economically challenged, and deeply Catholic in a way that can be either supportive or oppressive.

What was the grandmother’s life like? What was her emotional landscape? What were her relationships, her struggles, her joys? The article does not say. It assumes the answer lies in the gene.

But a growing body of research suggests that environment — including intergenerational environment — plays a crucial role. Research on the embodiment of intergenerational trauma has shown that parental disruption of the hypothalamic-pituitary-adrenal (HPA) axis — a key stress-response system — can lead to health complications in children, including “altered brain structure and gene expression” and “increased sensitivity to stress”. Epigenetic effects of trauma can be passed on to subsequent generations.10.

The grandmother’s resilience may have been shaped by her environment, her relationships, her life — not just her genes. The study does not ask this question.

Assumption 4: The “Phenocopy” Is an Inconvenient Asterisk.

The authors note that a relative meets full criteria for schizophrenia yet “may not carry the mutation at all” — a possible phenocopy.1. They “deliberately keep [the phenocopy] in the frame rather than dismiss as an inconvenient asterisk”.

But they still treat it as a puzzle to be solved, rather than as evidence that the model is wrong. If schizophrenia can occur without the variant, and the variant can occur without schizophrenia, then the variant is not the cause. It is a marker at best.

This is not a new observation. Research dating back to 2006 has identified phenocopies within schizophrenia pedigrees — individuals who meet diagnostic criteria without the family’s genetic marker — and suggested that these cases may represent a “continuum in which risk for schizophrenia-related cognitive impairments is highest among patients and relatives”.2. More recent research on traumatic brain injury (TBI) and schizophrenia found that “posttraumatic-brain-injury schizophrenia in multiplex schizophrenia pedigrees does not appear to be a phenocopy of the genetic disorder” — suggesting that environmental factors can interact with genetic vulnerability to produce illness.8.

The phenocopy is not an anomaly. It is evidence that the genetic model is incomplete.

Assumption 5: They Are Looking for a “Treatment Target.”

The stated hope is that “a handful of these rare variants will converge on a few downstream biological pathways, and that those pathways might one day yield treatments”.1.

This is the pharmaceutical paradigm: find the broken part, fix the broken part. But the broken part is not the gene. The broken part is the interpretation. And you cannot fix interpretation with a pill.

The assumption that a pill is the answer is not merely incomplete — it is dangerous. It reduces human experience to a broken gene and reduces treatment to a pharmaceutical intervention. It ignores the grandmother, who is well without a pill. It ignores the phenocopy, who is ill without the variant. It ignores the environment, the relationships, the life that shaped both.

IV. The Question They Will Not Ask

The study is being presented as a breakthrough — “a reminder that the most modern insight sometimes arrives by the oldest method we have, which is to sit down with a family and listen”.1.

But they are not really listening. They are measuring. They are sequencing. They are cataloguing.

They are not asking the question that matters: Why did the grandmother stay well when her grandchildren did not?

The answer is not in the gene.

The answer is in the grandmother’s life.

Her environment.

Her relationships.

Her resilience.

Her consciousness.

V. The Failure of Containment

There is a pattern in psychiatry that this study exemplifies: the reduction of human experience to biology, and the reduction of treatment to containment.

A diagnosis is not an explanation. It is a description. It tells us what a person is experiencing, not why. It is a starting point for inquiry, not an endpoint.

But the pharmaceutical paradigm treats diagnosis as the endpoint, and treatment as the containment of symptoms. A pill to silence the voices. A pill to stabilize the mood. A pill to suppress the anxiety.

This is not healing. It is containment.

The grandmother is well without containment.

The phenocopy is ill without the variant.

The environment — including the emotional environment — is ignored.

VI. A Glossary of Technical Terms

Term                                                                 Definition

CHD2                                                  A gene that helps build chromatin architecture during brain development; associated with childhood epilepsy, autism, and, as this study suggests, schizophrenia.

Founder Population                    A population descended from a small number of original settlers, resulting in reduced genetic diversity and making rare variants easier to detect.

Loss-of-Function Variant        A genetic mutation that prevents a gene from producing a functional protein.

Multiplex Family                            A family in which multiple members are affected by the condition being studied.

Phenocopy                                       An individual who exhibits the characteristics of a genetic disorder without carrying the associated genetic variant.

Resilience                                       The capacity to remain well despite significant genetic or environmental risk.

Endophenotype                            A measurable biological or cognitive trait that is associated with a genetic risk for a disorder, even in the absence of the disorder itself.

Epigenetics                                     The system of biochemical switches (methylation, histone modification, RNA activity) that activate or silence the expression of particular genes without changing the DNA sequence itself.

Hypothalamic-Pituitary-Adrenal (HPA) Axis              The body’s central stress-response system, which regulates cortisol production. Disruption of the HPA axis is associated with trauma and psychiatric disorders.

VII. Conclusion: The Grandmother’s Silence Speaks

This study is not without value. It confirms that diagnostic categories are fictions. It identifies a rare variant worth studying. It points to the grandmother, who should have been sick but was not.

But it fails to listen to what the grandmother is saying.

She is saying that the gene is not the cause.

She is saying that the environment matters.

She is saying that resilience is real.

She is saying that the reader — the organism, the person, the consciousness — matters more than the text.

The authors could have asked: What made her different? What protected her? What can we learn from her life, her relationships, her environment?

They did not.

Instead, they looked at her grandchildren, who carried the same gene and were not well — and they saw a “treatment target.”

This is the failure of psychiatry: the reduction of human experience to a broken gene, and the reduction of treatment to a pill.

It is a failure that presents a consistent pattern.

It is a failure that this study, for all its strengths, perpetuates.

The grandmother’s silence speaks louder than the gene.

It is time to listen.

Andrew Klein

References:

1. Pato CN, Pato MT, Mulle J, et al. Multiplex Portuguese families as a lens into rare mutations and the shared genetic architecture of schizophrenia, mood disorders, and autism spectrum disorders. Genomic Psychiatry. 2026. DOI: 10.61373/gp026h.0045.1.

2. Avila MT, Robles O, Hong LE, et al. Deficits on the Continuous Performance Test within the schizophrenia spectrum and the mediating effects of family history of schizophrenia. J Abnorm Psychol. 2006;115(4):771-8. 2.

3. Grotzinger A, et al. Multiple Psychiatric Disorders Share Genetic Roots. Nature. 2025. Cited in Medscape, December 19, 2025.4. 

4. Cahill S, et al. Genetic variants associated with resilience in humans and animals reaching consensus. Front Psychiatry. 2022;13:840120.5.

5. Yehuda R, et al. Embodiment and epigenetics of intergenerational trauma. In: Epigenetics of Stress and Trauma. 2022. Cited in epiAge, September 29, 2025.10. 

6. Malaspina D, et al. Traumatic Brain Injury and Schizophrenia in Members of Schizophrenia and Bipolar Disorder Pedigrees. Am J Psychiatry. 2001;158(3):440-446.8.