For decades, scientists have searched our DNA for clues that explain inherited risk. They have uncovered hundreds of genetic variants associated with type 2 diabetes, yet an important mystery remains. Some populations develop the disease far more frequently than others, and much of this difference cannot be explained by the genetic risk factors discovered so far.

This puzzle is especially important for people of South Asian ancestry. Individuals from the Indian subcontinent are significantly more likely to develop type 2 diabetes than people of European ancestry, often developing the disease at younger ages and lower body weights. Conventional genetic studies have only partially explained this increased susceptibility, suggesting that researchers may have been looking in the wrong places or overlooking important pieces of the genetic puzzle.

A study led by Prof. Dharambir Sanghera at the University of Oklahoma offers a compelling new perspective. Instead of concentrating solely on the common genetic variants that have dominated diabetes research for years, the team searched for much rarer changes hidden within families that have experienced diabetes across multiple generations. What they found suggests that some of the most important genetic influences on type 2 diabetes may lie not within the genes themselves, but within the stretches of DNA that control how those genes behave.

Even more remarkably, many of these rare variants appeared to be private to individual families. Rather than being widespread throughout the population, they were inherited within particular family lineages, making them almost invisible to large population studies. These findings demonstrate why studying families with unusually high rates of diabetes can reveal biological insights that might otherwise remain hidden.

For many years, genetic studies of type 2 diabetes have focused on common genetic variants. These are DNA differences that occur frequently throughout the population. Large international studies involving hundreds of thousands of participants have identified hundreds of these variants, allowing researchers to build what are known as polygenic risk scores. These scores estimate an individual’s inherited risk by combining the small effects of many common variants scattered throughout the genome.

Polygenic risk scores have become valuable tools for understanding disease susceptibility, and they continue to improve as more genetic data become available. Yet they have an important limitation. Even when hundreds of common variants are combined, they explain only part of a person’s inherited risk for developing type 2 diabetes. The unexplained portion appears to be particularly large in populations that have historically been underrepresented in genetic research.

Prof. Sanghera and her colleagues suspected that the missing answers might be hidden among rare genetic variants that conventional studies often fail to detect. To investigate this possibility, the researchers focused on Punjabi Sikh families from northern India. This population has a distinctive genetic history because marriages have traditionally occurred within the community over many generations. Such populations can preserve rare inherited variants that become concentrated within extended families, making them particularly valuable for studying the genetics of complex diseases.

The researchers examined thousands of individuals, including large multigenerational families in which type 2 diabetes repeatedly affected parents, children, grandparents, and siblings. Rather than scanning every letter of the genome, they concentrated on regions already known to influence diabetes risk, performing high resolution DNA sequencing to search for rare and ultra rare variants that earlier studies may have overlooked.

Their investigation revealed something unexpected. Several families carried rare variants in genes already known to play important roles in blood sugar regulation and insulin production, including HNF4A, ABCC8, and KCNJ11. These genes have long attracted scientific attention because inherited mutations within them can cause forms of monogenic diabetes known as Maturity Onset Diabetes of the Young, or MODY.

Classic MODY usually develops before the age of 25 and is caused by a harmful mutation in a single gene. The families in this study, however, did not fit that pattern. Instead of carrying one clearly responsible mutation, many family members possessed multiple rare variants spread across several diabetes related genes. Rather than behaving like a single inherited disorder, their diabetes appeared to arise from the combined influence of several genetic changes acting together.

This pattern, known as oligogenic inheritance, represents a more complicated picture of disease than researchers have traditionally considered. Instead of one mutation determining whether a person develops diabetes, multiple rare variants may gradually increase vulnerability until disease becomes more likely.

One family illustrated this idea particularly well. Family members carried an unusually high number of rare variants distributed across several important diabetes genes, and many of the people carrying these variants had developed type 2 diabetes. The findings suggested that the cumulative burden of rare variants, rather than any single mutation alone, may substantially influence disease risk.

Yet perhaps the most important discovery was not simply that these variants were rare, but where they were found. Most people imagine genes as stretches of DNA that contain instructions for building proteins, the molecules that perform much of the work inside our cells. Surprisingly, however, only a small fraction of the human genome actually codes for proteins. The vast majority consists of non-coding DNA, regions that do not build proteins themselves but instead help determine when genes are switched on, switched off, or how strongly they are expressed.

For many years, these non-coding regions attracted far less attention than protein coding genes. Today, scientists increasingly recognize that they function as sophisticated control systems for the genome. Small alterations within these regulatory regions can have profound biological consequences without changing the proteins themselves.

This is exactly what Prof. Sanghera’s team found. Most of the rare variants associated with diabetes in these families were located in non-coding regions rather than in the portions of DNA responsible for making proteins. Instead of altering the structure of a protein, these variants appeared to influence how genes are regulated. In other words, they changed the biological instructions that determine when important genes become active and how strongly they function.

This finding represents an important shift in our understanding of inherited disease. Rather than viewing non-coding DNA as inactive or unimportant, researchers increasingly recognize it as one of the genome’s most sophisticated regulatory systems. Changes within these regions may quietly reshape biological processes over many years, ultimately increasing the likelihood of diseases such as type 2 diabetes.

The team explored this possibility further by examining one particularly interesting variant within the ABCC8 gene.

Rather than simply identifying this rare variant through genetic sequencing, the researchers wanted to understand whether it actually changed how the gene functioned. Laboratory experiments showed that the variant altered the binding of proteins known as transcription factors. These proteins act like molecular switches, attaching to DNA and helping determine whether nearby genes are activated or silenced. By changing how these regulatory proteins interacted with the DNA, the non-coding variant influenced the gene’s activity without changing the protein that the gene ultimately produces.

The researchers also found evidence that some of these regulatory variants could influence the activity of transcription factors that respond to environmental influences such as toxins, pollutants, and high-fat diets. This raises the intriguing possibility that certain inherited variants may make some people more sensitive to environmental exposures than others. Although much more research is needed to understand these complex interactions, the findings suggest that genetics and lifestyle may work together in ways that are more interconnected than previously appreciated.

The study also highlighted the remarkable genetic diversity that exists within India itself. Although India is often discussed as a single population, it is home to thousands of communities with distinct cultural and genetic histories. Many groups have remained relatively isolated over generations, allowing unique genetic variants to emerge and persist within particular families or regions.

This became clear when the researchers compared families from different parts of India. Some rare variants identified in Punjabi Sikh families were also found among families from Rajasthan in northern India. However, many were absent in groups from southern India. Even more strikingly, several of the variants appeared to be entirely private to individual families, meaning they were not found elsewhere in the wider population.

These family-specific variants reinforce one of the study’s central messages. The genetics of type 2 diabetes cannot always be understood by examining large numbers of unrelated individuals alone. Some of the most informative genetic changes are so uncommon that they may only become visible when scientists carefully investigate families in which diabetes has been passed from one generation to the next.

This also helps explain one of the study’s most surprising findings. Because these families had such a strong history of diabetes, the researchers expected them to have very high polygenic risk scores. Instead, many family members had surprisingly modest scores. According to existing models based largely on common genetic variants, they did not appear to be at exceptionally high inherited risk.

Yet many had developed type 2 diabetes. The explanation seems to lie in the rare non-coding variants uncovered during the study. Polygenic risk scores are designed to measure the cumulative influence of common variants that are shared across large populations. They are not designed to capture the impact of family specific rare variants that may exert much stronger effects within a single lineage. In other words, these families carried an important form of inherited risk that conventional genetic scoring systems largely failed to detect.

This finding has important implications for the future of genetic medicine. A person may receive a relatively reassuring polygenic risk score while still carrying rare regulatory variants that substantially increase their likelihood of developing disease. These variants do not alter the underlying genetic code for proteins. Instead, they influence gene regulation through changes in the genome’s control regions, affecting processes such as transcription factor binding and other epigenetic mechanisms that determine how genes are expressed.

As genetic sequencing becomes increasingly affordable, incorporating rare non-coding variants into future risk assessments could provide a much more complete picture of inherited susceptibility, particularly for populations that have been underrepresented in previous genetic studies.

The broader significance of this research extends well beyond type 2 diabetes. The study demonstrates the extraordinary scientific value of investigating families with unusually high rates of disease. These families act as natural experiments, allowing researchers to uncover biological mechanisms that may remain hidden in studies involving hundreds of thousands of unrelated individuals. Those discoveries may eventually lead to improved screening methods, earlier diagnosis, and more precisely targeted treatments.

The work also highlights a longstanding imbalance in human genetics research. Historically, most large genetic studies have focused on people of European ancestry. As a result, scientists know considerably more about inherited disease risk in those populations than they do in many other parts of the world.

Research involving diverse populations helps close this gap. It broadens our understanding of human biology while ensuring that future advances in precision medicine can benefit people from every background rather than only those whose genetics have been studied most extensively.

Prof. Dharambir Sanghera and her colleagues believe that investigating families from underrepresented populations is essential for uncovering previously hidden disease mechanisms. Their work demonstrates that some of the most informative genetic discoveries emerge when researchers look beyond common variants and examine the rare inherited changes that can accumulate within individual families.

For patients and families affected by diabetes, these discoveries offer genuine hope. Every new insight into the biology of the disease brings researchers closer to more accurate prediction, earlier intervention, and treatments tailored to an individual’s unique genetic profile.

What began as an effort to explain why diabetes runs so strongly through a handful of families has evolved into a broader lesson about human genetics itself. Sometimes the greatest discoveries are found in the rare inherited variations that distinguish individual families. Understanding those hidden variations may ultimately illuminate disease processes for all of us.