Ekaterina Pesheva, Harvard Gazette, January 14, 2019

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Now a team of investigators from Harvard Medical School (HMS) and the University of Queensland in Australia have tackled this question in a decidedly novel way.

In what the researchers describe as a coup for big data and a scientific first, the team has used a massive insurance database of nearly 45 million people in the U.S., including thousands of twin pairs, to determine the effects of genes and environment in 560 common conditions. The diseases analyzed span 23 categories, ranging from cardiovascular illness and neuromuscular diseases to skeletal conditions.

The work, published Jan. 14 in Nature Genetics, is thought to be the largest assessment of U.S. twins to date, the researchers said. It is also the first one to go beyond the traditional one-disease-at-a-time approach and analyze hundreds of the most common conditions among more than 56,000 twin pairs. {snip}

Many diseases are neither purely genetic nor purely environmental, but rather the result of a complex interplay between the two. Unlike classic inherited conditions — those caused strictly by mutations in a gene or a set of genes — environmentally fueled conditions are the sole result of factors external to an individual’s biology. Most diseases do not fall neatly in either category but have elements of both. Disentangling how genes and environment contribute to multiple diseases in the same population has been astoundingly difficult, the researchers said. {snip}

The condition with the strongest potential link to socioeconomic status was morbid obesity.

“The nurture-versus-nature question is very much at the heart of our study. We foresee the value of this type of large-scale analysis will be in shining light on the relative contribution of genes versus shared environment in a multitude of diseases,” said senior study author Chirag Patel, assistant professor of biomedical informatics in the Blavatnik Institute at HMS.

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“Our findings can provide signposts that inform subsequent research efforts and help scientists narrowly focus their pursuits,” said study first author Chirag Lakhani, a postdoctoral research fellow in biomedical informatics at the Blavatnik Institute. “For example, if our study of twins shows that there is very little heritability effect in a certain family of eye disorders, then future research should pursue alternative explanations.”

Using the database of 45 million-plus patient records — which also included more than 724,000 sibling pairs — the investigators estimated the influence of genes and environment in fraternal twins, who share half of their genome, or DNA, and identical twins, whose DNA is 100 percent the same. Same-sex twins can be either identical or fraternal, while opposite-sex twins are always fraternal, but the researchers did not know which same-sex pairs were identical. To circumvent this hurdle, they developed a novel statistical method that inferred the probability that a pair of twins was fraternal (non-identical) or identical. In doing so, the researchers were able to separate purely genetic from nongenetic contributions.

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Nearly 40 percent of the diseases in the study (225 of 560) had a genetic component, while 25 percent (138) were driven at least in part by factors stemming from sharing the same household, social influences, and the like. Cognitive disorders demonstrated the greatest degree of heritability — four out of five diseases showed a genetic component — while connective tissue diseases had the lowest degree of genetic influence. Of all disease categories, eye disorders carried the highest degree of environmental influence, with 27 of 42 diseases showing such effect. They were followed by respiratory diseases, with 34 out of 48 conditions showing an effect from sharing a household. The disease category with lowest environmental influence was reproductive illnesses, with three of 18 conditions showing such effect, and cognitive conditions, with two out of five showing an influence.

Overall, socioeconomic status, climate conditions, and air quality in each twin pair’s ZIP code had a far weaker effect on disease than genes and shared environment — a composite measure of external, nongenetic influences including family and lifestyle, household, and neighborhood.

In total, 145 of 560 diseases were modestly influenced by socio-economic status derived by ZIP code. Thirty-six diseases were influenced at least in part by air quality, and 117 were affected by changes in temperature. The condition with the strongest potential link to socioeconomic status was morbid obesity. While obesity undoubtedly has a genetic component, the researchers said, the findings raise an important question about the influence of environment on genetic predispositions.

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When researchers looked at classes of diseases by monthly health care spending, they found that both genes and environment significantly contributed to cost of care, with the two being nearly equal drivers of spending. Almost 60 percent of monthly health spending could be predicted by analyzing genetic and environmental factors.

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[Editor’s Note: The complete study is available here.]