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Illustration of runs of homozygosity for affected and unaffected siblings
Credit: Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism

It is generally understood that inbreeding has some negative biological consequences for complex animals. Recessive diseases are the most straightforward. The rarer a recessive disease is the higher and higher fraction of sufferers of that disease will be products of pairings between relatives (the reason for this is straightforward, as extremely rare alleles which express in a deleterious fashion in homozygotes will be unlikely to come together in unrelated individuals). But when it comes to traits associated with inbred individuals recessive diseases are not what comes to mind for most, the boy from the film Deliverance is usually the more gripping image (contrary to what some of the actors claimed the young boy did not have any condition).

Some are curious about the consequences of inbreeding for a trait such as intelligence. The scientific literature here is somewhat muddled. But it seems likely that all things equal if two people of average intelligence pair up and are first cousins the I.Q. of their offspring will be expected to be 0-5 points lower than would otherwise be the case. By this, I mean that the studies you can find in the literature suggest when correcting for other variables that the inbreeding depression on the phenotypic level is greater than 0 (there is an effect) but less than 5 (it is not that large, less than 1/3 of a standard deviation of the trait value). Presumably for higher levels of inbreeding the consequences are going to be more dire.

But what about genetic homogeneity that’s not due to inbreeding? Recall that the recent Ralph and Coop paper showed empirically that there were many networks of genetic relatedness between people who one might think are absolutely unrelated. Anyone who uses 23andMe has plenty of evidence of this, as “relatives” begin to pop up who match genetic segments with you. If you have one line of descent from an individual far in the past you are often going to have another. This means that segments of DNA from the same individual may come “back together” and form a homozygous block. How this occurs for inbred individuals is simple. If your parents are first cousins they share one pair of grandparents, and each of these grandparents has two short lines of descent down to you. But this same dynamic applies in diluted form to those who are much further back in your genealogy. You may be entirely outbred in a pedigree sense, but still have runs of homozygosity due to chance.

A new paper in AJHG compares levels of runs of homozygosity in a data set of unaffected parents, unaffected offspring, and affected offspring. In particular the authors had a data set in the thousands of families who participated in autism research. The affected siblings were diagnosed with autism, while the parents and unaffected siblings did not exhibit the condition. In addition to autism there was a range in intelligence of the affected siblings. This experimental design is useful because you are comparing siblings who share a great deal genetically, but are phenotypically different. You have to correct for fewer confounds because their genetic backgrounds overlap, and, their environments are highly correlated.

Of course siblings are similar genetically, they are not duplicates. The expected relationship of siblings is 50%, but there is a variation in this value, and obviously there are genetic differences with the unrelated balance. In this study the authors focused on runs of homozygosity (ROH), which are likely due to ancestors showing up across their lineage at some distant time in multiple instances. Their minimum threshold for serious ROH blocks were relatively short at 2,500 kb (the expected value for how far back the common ancestor responsible for the ROH block of 2,500 is ~1,000 years). The topline find is that very low I.Q. affected siblings (<70, what would be termed “mentally retarded” in the past) had 1.32 times more ROH of > 2,500 kb (p = 0.03). They did not find a statistically significant different >70. The authors did a range of manipulations and slicing and dicing of the data. I am not particularly interested in those hoary details.

Rather, I’m heartened that high density SNP chips are now being applied to these sorts of massive family based studies, and the biological differences between siblings can be more properly assessed. There is a great deal of randomness across siblings in terms of their genetic inheritance. Two of my siblings only share 41% of their genes identical by descent (as opposed to the expected 50%). Not only that, I know that frequency of ROH also varies randomly across siblings; they do across mine. If the number of de novo point mutations of significant effect is on the order of 30 or so per individual then again variation across sibling cohorts is liable to be significant and of note.

Issues such as inbreeding depression or the phenotypic consequences of homozygosity were until recently theoretical matters, or explored in organisms such as Drosophila. That age is coming to an end. High coverage whole genome sequencing is going to allow for precise and powerful comparisons across sibling cohorts, and as whole nations go “all in” the swell of data is going to be awesome. I suppose people will find out things that they may be uncomfortable with, but one ultimately has to face up to the truth in the end.

Addendum: On a converse note, here’s a case where you seem to see outbreeding depression. On the genome-wide scale I’d be willing to bet this is less of a problem than inbreeding. And no, I am not convinced by the fact that there seems to be higher fertility in more closely related individuals in Iceland.

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In the links below I alluded to a controversy over the “Neurodiversity movement”. The basic issue is that people with Asperger syndrome and high functioning autism are being accused of putting their concerns above and beyond those of the large number of mentally disabled autistic individuals (some of whom are non-verbal, and exhibit severe cognitive deficits) in the grab for “rights.” Rights here understood as the rights which black Americans, women, and gays have claimed, to be recognized as equal before the law and endowed with the same value in the eyes of society. As a deep philosophical matter I’m skeptical of Rights in a fundamental sense. As a conservative I’m skeptical of the push for a huge array of rights by a plethora identity groups. Socially recognized rights are valuable, and are cheapened and debased by dispensing them too liberally.

For me the reality is that a functional society is one which has to assume as normative the preferences of the majority as being the guides for its proper organization, especially in cases where those preferences exhibit a strong innate aspect. Personally I find the social ticks of those with Asperger syndrome somewhat charming, and individuals who lack total social grace are often the best intellectual interlocutors. But it is implausible that we have to accept that many people on the extreme low social intelligence end of the spectrum are part of the “normal” range. Oddballs can find their place, and have their own dignity, but oddballs are oddballs (I speak as an oddball myself who assimilates with some impatience and reluctance to many of the norms of the mainstream).

Autism and many cognitive/behavioral syndromes are highly heritable, but their genetic underpinnings are only weakly understood. But over the last few years the more powerful sequencing technologies are finally starting to yield something interesting. In particular it seems likely that these syndromes and behavioral types are the result of innumerable low frequency variants. Many of them may also be de novo, and part of the reason why paternal age is so important in predicting these tendencies in offspring.

Two new papers in Neuron (both open access) highlight the current area of inquiry, Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders and Using Whole-Exome Sequencing to Identify Inherited Causes of Autism. I won’t go over the gory details. But even if you aren’t versed in medical genetics I assume “complete knockouts” does not have a positive connotation? Now mind you “wild type” is a subjective human construct. What is a deleterious mutation in one context may be a positive one in another. But I am not one to pussyfoot around, after all, I’ve admitted to the controversial proposition (to some) that Down syndrome is bad. Similarly, I think a lot of severe autism sufferers are suffering, and the genetic variations which are the cause of that suffering are bad. There are very brilliant high functioning autistic individuals who leverage their cognitive profile into virtuosity in their specialized knowledge domain. But these people are exceptional.

And yet I do wonder if those who promote neurodiversity will take heart in the fact that their cognitive profiles are genetically grounded? The “born that way” argument is very compelling in our society, and genes have social power. If you suggest that perhaps the phenotypes of autistic individuals is due to higher mutational load there is an immediate pop culture reference one can leverage in the X-Men, where marking off those with biophysical differences due to genetic novelty is rendered as unjust.

We live in interesting times.

• Category: Science • Tags: Autism, Genetics, Human Genetics, Human Genomics 
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My post below on atheism and autism caused some confusion. I want to quickly clear up some issues in regards to the model which I had in mind implicitly. In short I’m convinced by the work of cognitive scientists of religion (see Religion Explained and In Gods We Trust) that belief in gods and spirits is intuitively plausible to most people. It does not follow from this that when you have an intuitive belief that that belief is unshakable. This explains the variation in levels of atheism across societies as well as shifts of views across one’s lifetime. But, it also explains why in pre-modern societies acceptance of supernatural entities is the null or default position, if not necessarily universal.

But what’s the basis for the idea that belief in gods is intuitive? To reduce a lot of results down to a few sentences, humans live in a universe of other actors, agents, which we preoccupy over greatly. Additionally, we can conceive of agents which aren’t present before us. In other words, the plausibility of supernatural narratives derives from our orientation toward populating the universe with social beings and agency. There’s a lot of evolutionary psychological models for why this phenotype is adaptive, but that’s not relevant to us here. The point is that religious beliefs and systems use these intuitions and impulses as atoms with which they can build up more complex cultural ideas.

This is why autistic individuals are of particular interest. They either lack, or are highly deficient in, a great deal of naive social intelligence. If the root source of religiosity is a minimum level of social awareness of other agents, then one might suppose that autistic people may have difficulty finding supernatural agents, gods, plausible. Above I stated that I personally found the work of cognitive scientists of religion about the root causes of this phenomenon plausible. The reason I stated it in this way is that I’m one of the minority of human beings who has never found supernatural agents or spirits plausible. I had to read in a book why other people found gods so compelling as a concept. Reflectively I understood the gist, and I was indoctrinated in their existence as a small child, but these entities were never “real” to me. I suspect that this is due to a more global deficit in modeling other agents.

This is why the empirical results on the correlation between atheism and high functioning autism are important. High functioning autistic individuals are a “boundary condition” of normal human psychological function, and if conventional religiosity is strongly dependent on normal human psychology you would expect it to be generally lacking among high functioning autistic individuals. When I say conventional religiosity, I’m leaving an opening for unconventional religiosity. There are stories of autistic children when told of the concept of the afterlife who formulate a plan to kill themselves, because they accept at face value the promise of a utopian afterlife. This is not the normal human reaction, and it goes to the complexity of cognition, where multiple inconsistent views can be hold together simultaneously. But, I do think that a subset of religious fundamentalists are in fact the inversions of the atheists who find religion implausible on the face of it. To be plain about it, the beliefs of most religious systems imply a lot of crazy things if you work out the logic. But most people don’t behave in a crazy manner.

Also, as I noted below the psychological profile of atheism is going to vary by society, because the proportions of atheists varies. In a culture where religion is strongly normative, such as Palestine, atheism will be espoused by a particular personality profile willing to go against a very strong grain. In contrast, in a nation like Estonia there will be little difference between atheists and theists.

Finally, some people were angry that I seemed to suggest that atheists were antisocial weirdos. Well, there is some data to back that up. This doesn’t mean that more atheist societies are worse than more theist societies (e.g., Estonia vs. Romania). But when it comes to individual differences this seems robust in many societies, though probably not all. I’m curious if people who are aghast at my generalization have a lot of experience in person with atheist organizations? (I do)

• Category: Science • Tags: Atheism, Autism, Religion 
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Independent and dependent contributions of advanced maternal and paternal ages to autism risk:

Reports on autism and parental age have yielded conflicting results on whether mothers, fathers, or both, contribute to increased risk. We analyzed restricted strata of parental age in a 10-year California birth cohort to determine the independent or dependent effect from each parent. Autism cases from California Department of Developmental Services records were linked to State birth files (1990-1999). Only singleton births with complete data on parental age and education were included (n=4,947,935, cases=12,159). In multivariate logistic regression models, advancing maternal age increased risk for autism monotonically regardless of the paternal age. Compared with mothers 25-29 years of age, the adjusted odds ratio (aOR) for mothers 40+ years was 1.51 (95% CI: 1.35-1.70), or compared with mothers <25 years of age, aOR=1.77 (95% CI, 1.56-2.00). In contrast, autism risk was associated with advancing paternal age primarily among mothers <30: aOR=1.59 (95% CI, 1.37-1.85) comparing fathers 40+ vs. 25-29 years of age. However, among mothers >30, the aOR was 1.13 (95% CI, 1.01-1.27) for fathers 40+ vs. 25-29 years of age, almost identical to the aOR for fathers <25 years. Based on the first examination of heterogeneity in parental age effects, it appears that women’s risk for delivering a child who develops autism increases throughout their reproductive years whereas father’s age confers increased risk for autism when mothers are <30, but has little effect when mothers are past age 30. We also calculated that the recent trend towards delayed childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.

See ScienceDaily for more detail.

• Category: Science • Tags: Autism 
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Geographic distribution of autism in California: a retrospective birth cohort analysis:

Prenatal environmental exposures are among the risk factors being explored for associations with autism. We applied a new procedure combining multiple scan cluster detection tests to identify geographically defined areas of increased autism incidence. This procedure can serve as a first hypothesis-generating step aimed at localized environmental exposures, but would not be useful for assessing widely distributed exposures, such as household products, nor for exposures from nonpoint sources, such as traffic.

Geocoded mothers’ residences on 2,453,717 California birth records, 1996-2000, were analyzed including 9,900 autism cases recorded in the California Department of Developmental Services (DDS) database through February 2006 which were matched to their corresponding birth records. We analyzed each of the 21 DDS Regional Center (RC) catchment areas separately because of the wide variation in diagnostic practices. Ten clusters of increased autism risk were identified in eight RC regions, and one Potential Cluster in each of two other RC regions.

After determination of clusters, multiple mixed Poisson regression models were fit to assess differences in known demographic autism risk factors between the births within and outside areas of elevated autism incidence, independent of case status.

Adjusted for other covariates, the majority of areas of autism clustering were characterized by high parental education, e.g. relative risks >4 for college-graduate vs. nonhigh-school graduate parents. This geographic association possibly occurs because RCs do not actively conduct case finding and parents with lower education are, for various reasons, less likely to successfully seek services.

More from ScienceDaily:

However, the researchers said that in this investigation the clusters probably are not correlated with specific environmental pollutants or other “exposures.” Rather, they correlate to areas where residents are more educated.
“What we found with these clusters was that they correlated with neighborhoods of high education or neighborhoods that were near a major treatment center for autism,” said senior author Irva Hertz-Picciotto, a professor of public health sciences and a researcher with the UC Davis MIND Institute.

“In the U.S., the children of older, white and highly educated parents are more likely to receive a diagnosis of autism or autism spectrum disorder. For this reason, the clusters we found are probably not a result of a common environmental exposure. Instead, the differences in education, age and ethnicity of parents comparing births in the cluster versus those outside the cluster were striking enough to explain the clusters of autism cases,” Hertz-Picciotto said.

Van Meter said that the increased risk of autism in these areas is roughly a doubling of the incidence of autism over the incidence in the surrounding zone. For example, for the cluster area located in the service zone of the San Diego Regional Center, the autism incidence was 61.2 per 10,000 births and, in the rest of the Regional Center service zone, 27.1 per 10,000 births. For the Harbor Regional Center the incidence was 103.4 and 57.8, respectively. Van Meter added that it is important to remember that most of the children with autism were not born in the cluster areas.

In Southern California, the areas of increased incidence were located within these Regional Center service zones:

1. The Westside Regional Center, headquartered in Culver City, Calif., which serves the communities of western Los Angeles County, including the cities of Culver City, Inglewood and Santa Monica;

2. The Harbor Regional Center, headquartered in Torrance, Calif., which serves southern Los Angeles County, including the cities of Bellflower, Harbor, Long Beach and Torrance;

3. The North Los Angeles County Regional Center, headquartered in Van Nuys, Calif., which serves the San Fernando and Antelope valleys — two clusters were located in this regional center’s service zone.

4. The South Central Los Angeles Regional Center, headquartered in Los Angeles, which serves the communities of Compton and Gardena;

5. The Regional Center of Orange County, headquartered in Santa Ana, Calif., which serves the residents of Orange County; and

6. The Regional Center of San Diego County, headquartered in San Diego, which serves people living in Imperial and San Diego counties.

In Northern California, the areas of increased incidence were located within these regional centers’ service zones:

7. The Golden Gate Regional Center, headquartered in San Francisco, which serves Marin and San Mateo counties and the City and County of San Francisco. Two clusters were located within the Golden Gate Regional Center’s service zone; and

8. The San Andreas Regional Center, headquartered in Campbell, Calif., which serves Santa Clara, Santa Cruz, Monterey and San Benito counties.

Two areas of increased incidence were located in Central California regional centers’ service zones:

9. The Central Valley Regional Center, headquartered in Fresno, Calif., which serves Fresno, Kings, Madera, Mariposa, Merced and Tulare counties; and

10. The Valley Mountain Regional Center, headquartered in Stockton, Calif., which serves Amador, Calaveras, San Joaquin, Stanislaus and Tuolumne counties.

Might want to revisit an old Wired piece, The Greek Syndrome, from the early aughts.

• Category: Science • Tags: Autism 
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Tyler Cowen and Will Wilkinson in discussed Tyler’s most recent book, Create Your Own Economy, in a recent Tyler mentions how he believes there are a diversity of “cognitive profiles” out there, and that the autism spectrum oversimplifies and pathologizes one aspect of this reality. One feature of the modal human cognitive profile which Tyler seems to suggest might be somewhat suboptimal for information processing and gathering is the tendency to construct stories or narratives (because of the distortions that a general story arc might introduce into one’s perception of the facts). What struck me was a personal datum which I’ve never thought too deeply about until now: I never read fiction outside of assigned schoolwork until I was 13. The only exception to this was Greek mythology (e.g., The Iliad). Of course I did read a lot, but it was all non-fiction. In later years I came to understand that this was atypical. When I did start reading fiction almost all of it was science fiction, fantasy or historical fiction. To this day I have a very attenuated interest in conventional mainstream fiction. I suspect a large number of readers of this weblog can recount similar experiences.

One point of Will & Tyler’s diavlog which I might want to take issue with is the idea that specialization is a net benefit for most of humanity because they can find the particular occupational niche which leverages their strengths and satisfies their preferences. To some extent this is surely true, but to not put a too fine point on it I think the cost vs. benefit toward specialization is much greater for those on the “tails” of the cognitive spectrums; whether nerdy or arty. For a modal human who is more focused on concrete interpersonal dynamics I suspect “clocking in & out” at their job might not be unsatisfying since work is simply the time between socialization.

• Category: Science • Tags: Autism 
Razib Khan
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